iain mcgregor

Breaking the loop: oxytocin as a potential treatment for drug addiction.

Publisher: Elsevier BV

Date: 03-2011

DOI: 10.1016/J.YHBEH.2011.12.001

Abstract: Drug use typically occurs within a social context, and social factors play an important role in the initiation, maintenance and recovery from addictions. There is now accumulating evidence of an interaction between the neural substrates of affiliative behavior and those of drug reward, with a role for brain oxytocin systems in modulating acute and long-term drug effects. Early research in this field indicated that exogenous oxytocin administration can prevent development of tolerance to ethanol and opiates, the induction of stereotyped, hyperactive behavior by stimulants, and the withdrawal symptoms associated with sudden abstinence from drugs and alcohol. Additionally, stimulation of endogenous oxytocin systems is a key neurochemical substrate underlying the prosocial and empathogenic effects of party drugs such as MDMA (Ecstasy) and GHB (Fantasy). Brain oxytocin systems exhibit profound neuroplasticity and undergo major neuroadaptations as a result of drug exposure. Many drugs, including cocaine, opiates, alcohol, cannabis, MDMA and GHB cause long-term changes in markers of oxytocin function and this may be linked to enduring deficits in social behavior that are commonly observed in laboratory animals repeatedly exposed to these drugs. Very recent preclinical studies have illustrated a remarkable ability of exogenously delivered oxytocin to inhibit stimulant and alcohol self-administration, to alter associated drug-induced changes in dopamine, glutamate and Fos expression in cortical and basal ganglia sites, and to prevent stress and priming-induced relapse to drug seeking. Oxytocin therefore has fascinating potential to reverse the corrosive effects of long-term drugs abuse on social behavior and to perhaps inoculate against future vulnerability to addictive disorders. The results of clinical studies examining intranasal oxytocin effects in humans with drug use disorders are eagerly awaited. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.

‘When an old rat smells a cat’: A decline in defense-related, but not accessory olfactory, Fos expression in aged rats

Publisher: Elsevier BV

Date: 04-2011

DOI: 10.1016/J.NEUROBIOLAGING.2009.03.014

Abstract: Comparisons were made between young (3-6 months) and aged (20-30 months) Wistar rats on locomotor activity, emergence, social interaction and cat odor avoidance. Aged rats were less active and spent less time in the open field during the emergence test than younger rats. Older rats also showed fewer contacts with a novel conspecific in the social interaction test, although total duration of interaction did not differ. There were very few behavioral differences between male and female rats. Older rats were less reactive than younger rats in a test of cat odor avoidance. However, they expressed similar amounts of cat odor-induced Fos in the posterior accessory olfactory bulb, a critical region for processing the predator odor stimulus. Older rats had reduced Fos expression in several defense-related brain regions that are normally activated by predator odors such as the medial amygdala and dorsal premammillary nucleus. These results indicate that aged rats are less reactive than younger rats to predator odors due to decreased responsiveness in defense-related but not necessarily olfactory circuits.

Synthetic Cannabinoid Hydroxypentyl Metabolites Retain Efficacy at Human Cannabinoid Receptors

Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)

Date: 14-12-2018

DOI: 10.1124/JPET.118.254425

Analysis of Cannabis Seizures in NSW, Australia: Cannabis Potency and Cannabinoid Profile

Publisher: Public Library of Science (PLoS)

Date: 24-07-2013

DOI: 10.1371/JOURNAL.PONE.0070052

Comparative proteomics in the corpus callosal sub-regions of postmortem human brain

Publisher: Elsevier BV

Date: 12-2009

DOI: 10.1016/J.NEUINT.2009.04.017

Abstract: The corpus callosum (CC) is a single anatomical region with homologous cytoarchitecture and ided into four sub-regions such as the rostrum, the genu, the body and the splenium. Neuroimaging analysis revealed that susceptibility to clinical neurological diseases of these sub-regions is variable, indicating biochemical and physiological heterogenecity. To understand the biochemical make up of these regions, we compared the protein expression of these three sub-regional areas [the genu, the body and the splenium (n=9)] through 2D proteomics, which is a high-throughput global protein expression analysis technique. Normative proteomic comparison of gels, and analysis of spectra revealed that 17 (identified as 7 proteins), 35 (identified as 20 proteins) and 39 (identified as 21 proteins) protein spots were differentially expressed in the genu vs. the body, the genu vs. the splenium and the body vs. the splenium, respectively. These results suggest that the sub-regions of the CC differ at the level of protein expression. Identified proteins of the different groups belong to several functional classes such as cytoskeletal, metabolic, signaling, oxidative stress and calcium regulation. Interestingly, oxidative stress defense and glucose metabolic pathways of the splenium are quite different from the genu which might be correlated to region specific vulnerability of neuronal illness. Protein expression maps of these regions can be used as a reference source for future studies to investigate the molecular basis of functional differences and degree of pathogenesis of various neurodegenerative diseases of the CC.

From ultrasocial to antisocial: a role for oxytocin in the acute reinforcing effects and long‐term adverse consequences of drug use?

Publisher: Wiley

Date: 05-2008

DOI: 10.1038/BJP.2008.132

Neural Correlates of Cat Odor-Induced Anxiety in Rats: Region-Specific Effects of the Benzodiazepine Midazolam

Publisher: Society for Neuroscience

Date: 28-04-2004

DOI: 10.1523/JNEUROSCI.0187-04.2004

Abstract: Cat odor elicits a profound defensive reaction in rats that is reduced by benzodiazepine drugs. The neural correlates of this phenomenon were investigated here using Fos immunohistochemistry. Rats received either midazolam (0.75 mg/kg, s.c.) or vehicle and were exposed to pieces of a collar that had been worn by a domestic cat or an unworn (dummy) collar. Cat odor caused midazolam-sensitive defensive behavioral responses, including avoidance of collar contact, inhibition of grooming, and prolonged rearing. Cat odor exposure induced Fos expression in the posterior accessory olfactory bulb (glomerular, mitral, and granule cell layers), with granule cell layer activation attenuated by midazolam. High basal Fos expression, and some cat odor-associated Fos expression, was evident in the main olfactory bulb (glomerular cell layer), and midazolam exerted a strong inhibitory effect in this region. Midazolam inhibited Fos expression in key limbic regions involved in pheromone transduction (medial amygdala and bed nucleus of the stria terminalis) and defensive behavior (prelimbic cortex, lateral septum, lateral and medial preoptic areas, and dorsal premammillary nucleus). However, midazolam failed to affect cat odor-related Fos expression in a range of key defense-related sites, including the ventromedial hypothalamic nucleus, paraventricular nucleus of the hypothalamus, periaqueductal gray, and cuneiform nucleus. These results indicate that midazolam exerts a region-specific effect on the neural substrates activated by predator odor, with effects in the lateral septum and dorsal premammillary nucleus likely to be of major importance. These findings also suggest the intriguing hypothesis that cat odor is processed by rats as a “pheromone-like” stimulus.

MDMA ('Ecstasy') and methamphetamine combined: Order of administration influences hyperthermic and long-term adverse effects in female rats

Publisher: Elsevier BV

Date: 08-2005

DOI: 10.1016/J.NEUROPHARM.2005.03.002

Abstract: The acute and long-term dangers of 3,4-methylenedioxymeth hetamine (MDMA, 'Ecstasy') and meth hetamine (METH) are well described in idually, but their effect in combination is largely unknown. Here groups of female rats were given four MDMA or METH injections within a single session with each injection separated by 2h. Treatments included MDMA only, METH only, MDMA and METH in a cocktail (MDMA/METH), MDMA (two injections) followed by METH (two injections) (MDMA-->METH), or METH followed by MDMA (METH-->MDMA). Each injection involved 4mg/kg of total drug. Drug administration occurred at a high ambient temperature of 28 degrees C. All treatments produced hyperactivity while the treatments where MDMA was administered first (MDMA, MDMA-->METH and MDMA/METH) produced hyperthermia. All treatments involving METH caused significant head weaving. Six weeks after drug treatment all groups showed reduced social interaction relative to controls. MDMA/METH treatment was associated with reduced swimming in the forced swim test. MDMA given alone caused 5-HT depletion in several brain regions while METH given alone caused dopamine depletion in the striatum. The three treatments involving MDMA and METH combinations caused significant depletion of serotonin, dopamine and noradrenaline in several brain regions. Interestingly, the MDMA-->METH treatment produced greater hippoc al and cortical 5-HT depletion than the METH-->MDMA treatment suggesting an effect of order. These results extend our recent findings of additive toxic effects when METH is combined with MDMA. This has potentially important implications for party drug users who appear to frequently use this combination.

The safety and efficacy of low oral doses of cannabidiol: An evaluation of the evidence

Publisher: Wiley

Date: 19-10-2023

DOI: 10.1111/CTS.13425

Abstract: Global interest in the non‐intoxicating cannabis constituent, cannabidiol (CBD), is increasing with claims of therapeutic effects across a ersity of health conditions. At present, there is sufficient clinical trial evidence to support the use of high oral doses of CBD (e.g., 10–50 mg/kg) in treating intractable childhood epilepsies. However, a question remains as to whether “low‐dose” CBD products confer any therapeutic benefits. This is an important question to answer, as low‐dose CBD products are widely available in many countries, often as nutraceutical formulations. The present review therefore evaluated the efficacy and safety of low oral doses of CBD. The review includes interventional studies that measured the clinical efficacy in any health condition and/or safety and tolerability of oral CBD dosed at less than or equal to 400 mg per day in adult populations (i.e., ≥18 years of age). Studies were excluded if the product administered had a Δ 9 ‐tetrahydrocannabinol content greater than 2.0%. Therapeutic benefits of CBD became more clearly evident at doses greater than or equal to 300 mg. Increased dosing from 60 to 400 mg/day did not appear to be associated with an increased frequency of adverse effects. At doses of 300–400 mg, there is evidence of efficacy with respect to reduced anxiety, as well as anti‐addiction effects in drug‐dependent in iduals. More marginal and less consistent therapeutic effects on insomnia, neurological disorders, and chronic pain were also apparent. Larger more robust clinical trials are needed to confirm the therapeutic potential of lower (i.e., mg/day) oral doses of CBD.

The chemistry and pharmacology of putative synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS) 5F‐PY‐PICA, 5F‐PY‐PINACA, and their analogs

Publisher: Wiley

Date: 08-05-2019

DOI: 10.1002/DTA.2583

Abstract: 5F-PY-PICA and 5F-PY-PINACA are pyrrolidinyl 1-(5-fluoropentyl)ind (az)ole-3-carboxamides identified in 2015 as putative synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS). 5F-PY-PICA, 5F-PY-PINACA, and analogs featuring variation of the 1-alkyl substituent or contraction, expansion, or scission of the pyrrolidine ring were synthesized and characterized by nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-quadrupole time-of-flight-mass spectrometry (LC-QTOF-MS). In competitive binding experiments against HEK293 cells expressing human cannabinoid receptor type 1 (hCB

Reduced sensitivity to MDMA-induced facilitation of social behaviour in MDMA pre-exposed rats

Publisher: Elsevier BV

Date: 05-2008

DOI: 10.1016/J.PNPBP.2008.01.014

Abstract: The acute effects of the party drug 3,4-methylenedioxymeth hetamine (MDMA, "Ecstasy") in humans include feelings of love, closeness towards other people and an increased acceptance of others views and feelings. Some evidence suggests that regular MDMA users develop a subsensitivity to the positive effects of the drug and escalate their intake of the drug over time as a result. The current study investigated whether brief exposure to relatively high doses of MDMA in rats produces a subsequent attenuation in the ability of MDMA to enhance social interaction. Male Wistar rats were exposed to either MDMA (4 x 5 mg/kg over 4 h) or vehicle on two consecutive days. Twelve weeks later, MDMA pre-exposed rats displayed a significantly shorter period of time spent in social interaction than controls when tested in the drug-free state. MDMA pre-exposed rats also showed a blunted prosocial response to MDMA (2.5 mg/kg) relative to controls. This difference was overcome by increasing the MDMA dose to 5 mg/kg. The 5-HT(1A) agonist 8-OH-DPAT (250 microg/kg but not 125 microg/kg) increased social interaction and this effect did not differ in MDMA and vehicle pre-exposed rats. HPLC analysis showed a small but significant depletion of prefrontal 5-HT and 5-HIAA in MDMA pre-exposed rats. Prefrontal 5-HIAA concentrations were also reduced in the subset of vehicle and MDMA pre-exposed rats that received additional testing with MDMA. These results indicate that treatment with MDMA not only causes lasting reductions in social interaction in rats but causes an attenuation of the prosocial effects of subsequent MDMA administration. The lack of a differential response to 8-OH-DPAT agrees with other findings that the 5-HT(1A) receptor system remains functionally intact following MDMA pre-exposure and suggests that other neuroadaptations may underlie the lasting social deficits caused by MDMA.

Functional genomics of epilepsy-associated mutations in the GABAA receptor subunits reveal that one mutation impairs function and two are catastrophic

Publisher: Elsevier BV

Date: 04-2019

DOI: 10.1074/JBC.RA118.005697

Reintoxication: The release of fat-stored Δ ⁹- tetrahydrocannabinol (THC) into blood is enhanced by food deprivation or ACTH exposure

Publisher: Wiley

Date: 20-10-2009

DOI: 10.1111/J.1476-5381.2009.00399.X

Cortisol response and psychological distress predict susceptibility to false memories for a trauma film

Publisher: Informa UK Limited

Date: 23-10-2016

DOI: 10.1080/09658211.2015.1102287

Abstract: For eyewitness testimony to be considered reliable, it is important to ensure memory remains accurate following the event. As many testimonies involve traumatic, as opposed to neutral, events, it is important to consider the role of distress in susceptibility to false memories. The aim of this study was to investigate whether cortisol response following a stressor would be associated with susceptibility to false memories. Psychological distress responses were also investigated, specifically, dissociation, intrusions, and avoidance. Participants were allocated to one of three conditions: those who viewed a neutral film (N = 35), those who viewed a real trauma film (N = 35), and a trauma "reappraisal" group where participants were told the film was not real (N = 35). All received misinformation about the film in the form of a narrative. Participants provided saliva s les (to assess cortisol) and completed distress and memory questionnaires. Cortisol response was a significant predictor of the misinformation effect. Dissociation and avoidance were related to confabulations. In conclusion, following a stressor an in idual may differ with regard to their psychological response to the event, and also whether they experience a cortisol increase. This may affect whether they are more distressed later on, and also whether they remember the event accurately.

Combined low dose treatment with opioid and cannabinoid receptor antagonists synergistically reduces the motivation to consume alcohol in rats

Publisher: Springer Science and Business Media LLC

Date: 04-2004

DOI: 10.1007/S00213-003-1694-5

Abstract: Opioid and cannabinoid CB(1) receptor antagonists reduce the motivation to consume alcohol when taken in idually but their effectiveness in combination is not yet known. The effects of naloxone/naltrexone and SR 141716 alone and in combination were examined on beer consumption in rats. In a progressive ratio paradigm rats were trained to lick at a tube for either beer (4.5% ethanol v/v) or near-beer (beer containing <0.5% ethanol v/v) under a progressive ratio schedule of reinforcement. They were then tested with naloxone (0.3, 0.6 or 1.2 mg/kg i.p.), SR 141716 (0.15, 0.3 or 0.6 mg/kg i.p.) and their combination. In a continuous access paradigm, other rats were given beer or near-beer in their home cages for several weeks and the effects of repeated (4 day) administration of naltrexone (0.3, 0.6 or 1.2 mg/kg), SR 141716 (0.15, 0.3 or 0.6 mg/kg) and their combination were assessed. In the progressive ratio paradigm SR 141716, naloxone and their combination were more effective in reducing the break points for beer rather than near-beer. The two lowest dose combinations produced a synergistic reduction in break points. The highest dose combination reduced break points for both beer and near-beer and effects were more additive than synergistic. In the continuous access paradigm, the low doses of the drugs selectively reduced beer consumption in a synergistic fashion with higher doses having a less selective and more additive effect. The combined, low dose treatment has possible clinical efficacy in treating alcohol craving in humans.

Neuroadaptations in the striatal proteome of the rat following prolonged excessive sucrose intake

Publisher: Springer Science and Business Media LLC

Date: 15-03-2014

DOI: 10.1007/S11064-014-1274-6

Abstract: Obesity is a contemporary health problem of rapidly increasing prevalence. One possible cause of obesity is loss of control over consumption of highly palatable foodstuffs, perhaps mirroring the processes involved in drug addiction. Accordingly, the striatum may be a key neural substrate involved in both food and drug craving. We hypothesised here that prolonged exposure to 10% sucrose solution might cause neuroadaptations in the striatum that are analogous to those previously reported following prolonged exposure to alcohol or recreational drugs. Male Wistar rats were given constant access to 10% sucrose solution (in addition to normal lab chow and tap water) for 8 months and were compared with control rats receiving no sucrose access. Rats in the sucrose group typically drank more than 100 ml of sucrose solution per day and showed 13% greater body weight than controls at the end of the 8 months. Striatal dopamine (DA) concentrations were decreased in the sucrose group rats relative to controls. Differential expression of 18 proteins was identified in the striatum of the sucrose group rats relative to controls. Down regulated proteins included pyridoxal phosphate phosphatase, involved in DA synthesis, and glutathione transferase, involved in free radical scavenging. Up regulated proteins included prolactin (which is under negative regulation by DA) and adipose differentiation-related protein, involved in fat synthesis. We hypothesise that DA-related neuroadaptations in the striatum caused by prolonged sucrose intake may partly drive compulsive intake and seeking of high palatability foodstuffs, in a similar way to that observed with drug and alcohol addictions.

Resilience and reduced c-Fos expression in P2X7 receptor knockout mice exposed to repeated forced swim test

Publisher: Elsevier BV

Date: 08-2011

DOI: 10.1016/J.NEUROSCIENCE.2011.05.049

Abstract: There is considerable evidence suggesting genetic factors play an important role in the pathophysiology of depression, possibly by increasing susceptibility to repeated environmental stressors. Recent linkage studies have associated a polymorphism of the gene coding for the P2X7 receptor (P2X7R) with both major depressive disorder and bipolar disorder. Here we assessed whether P2X7 deletion affected the behavioural and neural response to repeated stress. P2X7R knockout (P2X7-/-) mice were subjected to the forced swim test for three consecutive days and neuronal activation in response to the third exposure was assessed using c-Fos immunohistochemistry. In addition, anxiety was evaluated in another group of P2X7-/- mice using the elevated plus maze (EPM) and light dark emergence (LDE) tests. Equivalent levels of immobility were observed in P2X7-/- mice and wild-type (WT) mice on the first exposure to forced swim, but much greater immobility was seen in WT mice on second and third exposures. This suggests that P2X7-/- mice exhibit an impaired adaptive coping response to repeated stress. Reinforcing this view, c-Fos expression in the dentate gyrus of the hippoc us and in the basolateral amygdala was seen in WT mice but not P2X7-/- mice following repeated forced swim. In addition, decreased locomotor activity was detected in P2X7-/- mice without any specific effects on anxiety in the LDE test. However, P2X7-/- mice showed greater anxiety-like behaviour in the EPM. These data suggest that the P2X7R may be involved in the adaptive mechanisms elicited by exposure to repeated environmental stressors that leads to the development of depression-like behaviours. This suggests that P2X7R antagonists may be useful therapeutics for the treatment of major depression, possibly by increasing resilience in the face of repeated stress.

The Cannabinoid Receptor Agonist THC Attenuates Weight Loss in a Rodent Model of Activity-Based Anorexia

Publisher: Springer Science and Business Media LLC

Date: 16-03-2011

DOI: 10.1038/NPP.2011.19

Inflammation and Breakdown of the Blood–Retinal Barrier During “Physiological Aging” in the Rat Retina: A Model for CNS Aging

Publisher: Wiley

Date: 2007

DOI: 10.1080/10739680601073451

Abstract: To examine the possible contribution of inflammation and breakdown of the blood-brain barrier in the central nervous system (CNS) of physiologically aged rats showing cognitive decline. Young (3- to 6-month-old) and aged (24- to 30-month-old) Wistar rats were assessed by the novel object recognition test. Vascular and inflammatory changes in the CNS were investigated in whole-mount preparations or sections of retinas from young adult or aged male Wistar rats. Aged rats showed a significant impairment in short-term memory compared with young adults. Deterioration of blood-retinal barrier function in aged rats was evidenced by leakage of intravascular tracer into the retinal parenchyma and reduced immunoreactivity for the tight junctional protein, occludin. Immunohistochemistry revealed the presence of major histocompatibility complex (MHC) class II-positive resident microglia, activated T cells, and monocyte-like cells in the retinal parenchyma of aged rats only. Microglia positive for the ED1 antigen, indicative of phagocytic activity, were also observed in these retinas. Breakdown of the blood-retinal barrier, MHC class II expression, microglial activation, and trafficking of activated T cells are associated with physiological aging. Such changes in the CNS may contribute to the pathogenesis of age-related cognitive decline.

Regional Fos-expression induced by γ-hydroxybutyrate (GHB): Comparison with γ-butyrolactone (GBL) and effects of co-administration of the GABAB antagonist SCH 50911 and putative GHB antagonist NCS-382

Publisher: Elsevier BV

Date: 09-2014

DOI: 10.1016/J.NEUROSCIENCE.2014.07.056

Abstract: γ-Hydroxybutyrate (GHB) has a complex array of neural actions that include effects on its own high-affinity GHB receptor, the release of neuroactive steroids, and agonist actions at GABAA and GABAB receptors. We previously reported partial overlap in the c-Fos expression patterns produced by GHB and the GABAB agonist, baclofen in rats. The present study extends these earlier findings by examining the extent to which GHB Fos expression and behavioral sedation are prevented by (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), a GABAB antagonist, and NCS-382, a putative antagonist at the high-affinity GHB receptor. We also compare Fos expression caused by GHB and its precursor γ-butyrolactone (GBL), which is a pro-drug for GHB but lacks the high sodium content of the parent GHB molecule. Both GHB (1,000 mg/kg) and GBL (600 mg/kg) induced rapid sedation in rats that lasted over 90 min and caused similar Fos expression patterns, albeit with GBL causing greater activation of the nucleus accumbens (core and shell) and dentate gyrus (granular layer). Pretreatment with SCH 50911 (100mg/kg) partly reversed the sedative effects of GHB and significantly reduced GHB-induced Fos expression in only four regions: the tenia tecta, lateral habenula, dorsal raphe and laterodorsal tegmental nucleus. NCS-382 (50mg/kg) had no effect on GHB-induced sedation or Fos expression. When given alone, both NCS-382 and SCH 50911 increased Fos expression in the bed nucleus of the stria terminalis, central amygdala, parasubthalamic nucleus and nucleus of the solitary tract. SCH 50911 alone affected the Islands of Calleja and the medial, central and paraventricular thalamic nuclei. Overall, this study shows a surprising lack of reversal of GHB-induced Fos expression by two relevant antagonists, both of which have marked intrinsic actions. This may reflect the limited doses tested but also suggests that GHB Fos expression reflects mechanisms independent of GHB and GABAB receptors.

Cannabidiol potentiates Δ ⁹-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats

Publisher: Springer Science and Business Media LLC

Date: 11-06-2011

DOI: 10.1007/S00213-011-2342-0

Abstract: The interactions between Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) during chronic treatment, and at equivalent doses, are not well characterised in animal models. The aim of this study is to examine whether the behavioural effects of THC, and blood and brain THC levels are affected by pre-treatment with equivalent CBD doses. Adolescent rats were treated with ascending daily THC doses over 21 days (1 then 3 then 10 mg/kg). Some rats were given equivalent CBD doses 20 min prior to each THC injection to allow examination of possible antagonistic effects of CBD. During dosing, rats were assessed for THC and CBD/THC effects on anxiety-like behaviour, social interaction and place conditioning. At the end of dosing, blood and brain levels of THC, and CB(1) and 5-HT(1A) receptor binding were assessed. CBD potentiated an inhibition of body weight gain caused by chronic THC, and mildly augmented the anxiogenic effects, locomotor suppressant effects and decreased social interaction seen with THC. A trend towards place preference was observed in adolescent rats given CBD/THC but not those given THC alone. With both acute and chronic administration, CBD pre-treatment potentiated blood and brain THC levels, and lowered levels of THC metabolites (THC-COOH and 11-OH-THC). CBD co-administration did not alter the THC-induced decreases in CB(1) receptor binding and no drug effects on 5-HT(1A) receptor binding were observed. CBD can potentiate the psychoactive and physiological effects of THC in rats, most likely by delaying the metabolism and elimination of THC through an action on the CYP450 enzymes that metabolise both drugs.

Δ⁹-THC reinstates beer- and sucrose-seeking behaviour in abstinent rats: Comparison with midazolam, food deprivation and predator odour

Publisher: Oxford University Press (OUP)

Date: 18-11-2005

DOI: 10.1093/ALCALC/AGH113

Abstract: Recent studies suggest that cannabinoid receptor agonists may promote relapse to drug-seeking behaviour after a period of abstinence. In this study, the ability of Delta(9)-tetrahydrocannabinol (THC) to reinstate previously reinforced responding for alcoholic and non-alcoholic beverages was assessed in rats using a novel lick-based paradigm. Rats were initially given free access to beer (containing 4.5% ethanol v/v), near-beer (a beverage that looks and tastes like beer but contains <0.5% ethanol v/v) or isocaloric sucrose in their home cages for 3 weeks. They were then trained to lick at a tube to self-administer the pre-exposed beverage in operant chambers under a VR10 schedule in 30-min sessions daily. After approximately 3 weeks of such access, the rats underwent an extinction procedure, so that licking at the tube produced no reward. Once responding had ceased, the rats were subjected to various reinstatement tests. In Experiment 1, the cannabinoid receptor agonist Delta(9)-THC (1 mg/kg) significantly reinstated responding, previously reinforced with beer or near-beer. The effect was unlikely to be caused by increased appetite because 24 h food-deprivation had no such effect. Exposure to cat odour in the test chamber failed to reinstate responding for beer or near-beer and caused a complete inhibition of responding. In Experiment 2, Delta(9)-THC (0.3 and 1 but not 3 mg/kg) again reinstated beer-seeking behaviour while the 1 mg/kg dose also reinstated responding in sucrose trained animals. Midazolam (0.15 mg/kg but not 0.5 or 1.5 mg/kg) produced a modest reinstatement of beer-seeking but had no effect on sucrose-seeking behaviour. The finding that Delta(9)-THC can reinstate alcohol-seeking provides the impetus for further research into the involvement of the cannabinoid system in alcohol craving. However, the reinstatement of near-beer and sucrose-seeking behaviour caused by Delta(9)-THC suggests a relatively non-specific effect. This may perhaps be related to the stressor-like effects of cannabinoids, and their ability to activate key neural circuitry in the amygdala and bed nucleus of the stria terminalis.

Cannabinoids increase conditioned ultrasonic vocalisations and cat odour avoidance in rats: Strain differences in drug-induced anxiety

Publisher: Elsevier BV

Date: 10-2010

DOI: 10.1016/J.LFS.2010.09.018

Abstract: Genetic disposition modulates the psychoactive effects of cannabis. Cannabinoids have a greater impact on brain regions that subserve anxiety in Wistar compared to Lewis strain rats. Here we aim to show that this correlates with strain differences in cannabinoid-induced anxiety-related behaviour. Lewis and Wistar rats were administered vehicle or the synthetic cannabinoid receptor agonist, CP 55,940 (10, 25 and 50μg/kg) before testing in the conditioned ultrasonic vocalization (USV), cat odour avoidance or open area avoidance models. Animals were placed in a chamber in which they had previously received footshock. Wistar but not Lewis rats re-exposed under the influence of all CP 55,940 doses emitted significantly more USVs than vehicle-treated rats. In the cat odour avoidance model, rats were exposed to cat odour and given the opportunity to hide in a small box. In Wistar but not Lewis rats, 50μg/kg of CP 55,940 magnified hiding behaviour promoted by cat odour exposure. Animals were also tested in the open area avoidance model which occurred in the same arena as the predatory avoidance model but without cat odour. In Wistar, but not Lewis rats, 25 and 50μg/kg of CP 55,940 increased the avoidance of the open space. CP 55,940 increased anxiety-related behaviour in Wistar rats but not Lewis rats providing a model to dissect the genetic basis of cannabinoid-induced anxiety. We show for the first time that cannabinoids magnify conditioned USVs and cat odour avoidance behaviour dependent on the strain being tested.

Cannabis use in patients 3 months after ceasing nabiximols for the treatment of cannabis dependence: Results from a placebo-controlled randomised trial

Publisher: Elsevier BV

Date: 10-2020

DOI: 10.1016/J.DRUGALCDEP.2020.108220

Oxytocin and vasopressin modulate the social response to threat: a preclinical study.

Publisher: Oxford University Press (OUP)

Date: 07-05-2014

DOI: 10.1017/S1461145714000388

Cannabinoid Replacement Therapy (CRT): Nabiximols (Sativex) as a Novel Treatment for Cannabis Withdrawal

Publisher: Wiley

Date: 17-04-2015

DOI: 10.1002/CPT.109

Abstract: Cannabis is a common recreational drug that is generally considered to have low addictive potential. However, an increasing number of cannabis users are seeking treatment for dependence on the drug. There is interest in using agonist (substitution) pharmacotherapies to treat cannabis dependence and here we outline a novel approach involving a buccal spray (nabiximols) that contains tetrahydrocannabinol (THC) and cannabidiol (CBD). We review recent research with nabiximols and highlight findings relevant to clinical practice.

Pharmacology of Valinate and tert-Leucinate Synthetic Cannabinoids 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and Their Analogues

Publisher: American Chemical Society (ACS)

Date: 27-07-2016

DOI: 10.1021/ACSCHEMNEURO.6B00137

Abstract: Indole and indazole synthetic cannabinoids (SCs) featuring l-valinate or l-tert-leucinate pendant group have recently emerged as prevalent recreational drugs, and their use has been associated with serious adverse health effects. Due to the limited pharmacological data available for these compounds, 5F-AMBICA, 5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-CHMICA, and their analogues were synthesized and assessed for cannabimimetic activity in vitro and in vivo. All SCs acted as potent, highly efficacious agonists at CB1 (EC50 = 0.45-36 nM) and CB2 (EC50 = 4.6-128 nM) receptors in a fluorometric assay of membrane potential, with a general preference for CB1 activation. The cannabimimetic properties of two prevalent compounds with confirmed toxicity in humans, 5F-AMB and MDMB-FUBINACA, were demonstrated in vivo using biotelemetry in rats. Bradycardia and hypothermia were induced by 5F-AMB and MDMB-FUBINACA doses of 0.1-1 mg/kg (and 3 mg/kg for 5F-AMB), with MDMB-FUBINACA showing the most dramatic hypothermic response recorded in our laboratory for any SC (>3 °C at 0.3 mg/kg). Reversal of hypothermia by pretreatment with a CB1, but not CB2, antagonist was demonstrated for 5F-AMB and MDMB-FUBINACA, consistent with CB1-mediated effects in vivo. The in vitro and in vivo data indicate that these SCs act as highly efficacious CB receptor agonists with greater potency than Δ(9)-THC and earlier generations of SCs.

The effect of COVID19 pandemic restrictions on an urban rodent population

Publisher: Springer Science and Business Media LLC

Date: 21-06-2021

DOI: 10.1038/S41598-021-92301-0

Abstract: Shortly after the enactment of restrictions aimed at limiting the spread of COVID-19, various local government and public health authorities around the world reported an increased sighting of rats. Such reports have yet to be empirically validated. Here we combined data from multi-catch rodent stations (providing data on rodent captures), rodent bait stations (providing data on rodent activity) and residents’ complaints to explore the effects of a six week lockdown period on rodent populations within the City of Sydney, Australia. The s ling interval encompassed October 2019 to July 2020 with lockdown defined as the interval from April 1st to May 15th, 2020. Rodent captures and activity (visits to bait stations) were stable prior to lockdown. Captures showed a rapid increase and then decline during the lockdown, while rodent visits to bait stations declined throughout this period. There were no changes in the frequency of complaints during lockdown relative to before and after lockdown. There was a non-directional change in the geographical distribution of indices of rodent abundance suggesting that rodents redistributed in response to resource scarcity. We hypothesize that lockdown measures initially resulted in increased rodent captures due to sudden shortage of human-derived food resources. Rodent visits to bait stations might not show this pattern due to the nature of the binary data collected, namely the presence or absence of a visit. Relocation of bait stations driven by pest management goals may also have affected the detection of any directional spatial effect. We conclude that the onset of COVID-19 may have disrupted commensal rodent populations, with possible implications for the future management of these ubiquitous urban indicator species.

Cannabinoids prevent the acute hyperthermia and partially protect against the 5-HT depleting effects of MDMA (Ecstasy) in rats

Publisher: Elsevier BV

Date: 06-2004

DOI: 10.1016/J.NEUROPHARM.2004.01.002

An Australian nationwide survey on medicinal cannabis use for epilepsy: History of antiepileptic drug treatment predicts medicinal cannabis use

Publisher: Elsevier BV

Date: 05-2017

DOI: 10.1016/J.YEBEH.2017.02.005

Abstract: Epilepsy Action Australia conducted an Australian nationwide online survey seeking opinions on and experiences with the use of cannabis-based products for the treatment of epilepsy. The survey was promoted via the Epilepsy Action Australia's main website, on their Facebook page, and by word of mouth. The survey consisted of 39 questions assessing demographics, clinical factors, including diagnosis and seizure types, and experiences with and opinions towards cannabis use in epilepsy. A total of 976 responses met the inclusion criteria. Results show that 15% of adults with epilepsy and 13% of parents/guardians of children with epilepsy were currently using, or had previously used, cannabis products to treat epilepsy. Of those with a history of cannabis product use, 90% of adults and 71% of parents reported success in reducing seizure frequency after commencing cannabis products. The main reasons for medicinal cannabis use were to manage treatment-resistant epilepsy and to obtain a more favorable side-effect profile compared to standard antiepileptic drugs. The number of past antiepileptic drugs tried was a significant predictor of medicinal cannabis use in both adults and children with epilepsy. Fifty-six percent of adults with epilepsy and 62% of parents/guardians of children with epilepsy expressed willingness to participate in clinical trials of cannabinoids. This survey provides insight into the use of cannabis products for epilepsy, in particular some of the likely factors influencing use, as well as novel insights into the experiences of and attitudes towards medicinal cannabis in people with epilepsy in the Australian community. This article is part of a Special Issue entitled "Cannabinoids and Epilepsy".

Oxytocin in the nucleus accumbens core reduces reinstatement of methamphetamine‐seeking behaviour in rats

Publisher: Wiley

Date: 16-11-2014

DOI: 10.1111/ADB.12198

Abstract: The psychostimulant meth hetamine (METH) is an addictive illicit drug. Systemic administration of the neuropeptide oxytocin modulates METH-related reward and METH-seeking behaviour. Recent findings demonstrated a reduction in METH-induced reward by oxytocin administration into the nucleus accumbens (NAc) core. It is not known, however, if oxytocin acts in this region to reduce relapse to METH-seeking behaviour. Using the drug reinstatement paradigm in rats experienced at METH self-administration, we aimed to determine whether oxytocin pre-treatment within the NAc core would reduce relapse to METH use and if this could be reversed by the co-administration of the oxytocin receptor (OTR) antagonist desGly-NH2,d(CH2)5[D-Tyr2,Thr4]OVT. Male Sprague-Dawley rats underwent surgery to implant an intravenous jugular vein catheter and bilateral microinjection cannulae in the NAc core. Rats were then trained to self-administer intravenous METH (0.1 mg/kg/infusion) by lever press during 2-hour fixed ratio 1 scheduled sessions for 20 days. Following extinction of lever press activity, the effect of microinjecting saline, oxytocin (0.5 pmol, 1.5 pmol, 4.5 pmol) or co-administration of oxytocin (1.5 pmol) and desGly-NH2,d(CH2)5[D-Tyr2,Thr4]OVT (1 nmol, 3 nmol) in the NAc core (500 nl/side) was examined on METH-primed (1 mg/kg, i.p.) reinstatement of drug-seeking behaviour. Our results showed oxytocin directly administered into the NAc core decreased METH-primed reinstatement in a dose-dependent manner. Co-administration of the selective OTR antagonist did not specifically reverse the inhibitory effects of oxytocin on METH priming, suggesting mediation by receptors other than the OTR. These findings highlight an important modulatory effect of oxytocin in the NAc core on relapse to METH seeking.

Cannabidiol and Sports Performance: a Narrative Review of Relevant Evidence and Recommendations for Future Research

Publisher: Springer Science and Business Media LLC

Date: 06-07-2020

DOI: 10.1186/S40798-020-00251-0

Abstract: Cannabidiol (CBD) is a non-intoxicating cannabinoid derived from Cannabis sativa . CBD initially drew scientific interest due to its anticonvulsant properties but increasing evidence of other therapeutic effects has attracted the attention of additional clinical and non-clinical populations, including athletes. Unlike the intoxicating cannabinoid, Δ 9 -tetrahydrocannabinol (Δ 9 -THC), CBD is no longer prohibited by the World Anti-Doping Agency and appears to be safe and well-tolerated in humans. It has also become readily available in many countries with the introduction of over-the-counter “nutraceutical” products. The aim of this narrative review was to explore various physiological and psychological effects of CBD that may be relevant to the sport and/or exercise context and to identify key areas for future research. As direct studies of CBD and sports performance are is currently lacking, evidence for this narrative review was sourced from preclinical studies and a limited number of clinical trials in non-athlete populations. Preclinical studies have observed robust anti-inflammatory, neuroprotective and analgesic effects of CBD in animal models. Preliminary preclinical evidence also suggests that CBD may protect against gastrointestinal damage associated with inflammation and promote healing of traumatic skeletal injuries. However, further research is required to confirm these observations. Early stage clinical studies suggest that CBD may be anxiolytic in “stress-inducing” situations and in in iduals with anxiety disorders. While some case reports indicate that CBD improves sleep, robust evidence is currently lacking. Cognitive function and thermoregulation appear to be unaffected by CBD while effects on food intake, metabolic function, cardiovascular function, and infection require further study. CBD may exert a number of physiological, biochemical, and psychological effects with the potential to benefit athletes. However, well controlled, studies in athlete populations are required before definitive conclusions can be reached regarding the utility of CBD in supporting athletic performance.

Oxytocin prevents ethanol actions at δ subunit-containing GABAA receptors and attenuates ethanol-induced motor impairment in rats.

Publisher: Proceedings of the National Academy of Sciences

Date: 23-02-2015

DOI: 10.1073/PNAS.1416900112

Abstract: Even moderate doses of alcohol can cause considerable motor impairment. This effect has been linked to ethanol-induced potentiation of GABA actions at δ subunit-containing GABA A receptors (δ-GABA A Rs). Here, we demonstrate that the neuropeptide oxytocin selectively attenuates ethanol-induced motor impairment in rats as well as ethanol-induced potentiation of GABAergic activity at δ-GABA A Rs. This effect of oxytocin is shown to be independent of the oxytocin receptor (OTR) and involves a direct action at δ-GABA A Rs. To our knowledge, this study provides the first evidence of oxytocin having a direct, non-OTR–mediated effect on GABA–ethanol interactions. Recent preclinical and clinical studies indicate that oxytocin may also attenuate alcohol consumption, craving, and withdrawal, and the present study shows a previously unidentified mechanism through which some of these effects may occur.

Increased anxiety and depressive symptoms months after MDMA (ecstasy) in rats: Drug-induced hyperthermia does not predict long-term outcomes

Publisher: Springer Science and Business Media LLC

Date: 08-2003

DOI: 10.1007/S00213-003-1452-8

Abstract: There is some uncertainty whether the acute hyperthermia caused by MDMA (ecstasy) plays a significant role in determining the long-term neurotoxic effects on brain 5-HT systems and associated changes in mood and behaviour. The present study assessed whether long-term behavioural and cognitive changes seen in MDMA-treated rats are affected by hyperthermia at the time of drug administration. Male Wistar rats were treated with MDMA (4x5 mg/kg i.p. over 4 h on 2 consecutive days) or vehicle at either a high ambient temperature (28 degrees C) or a low ambient temperature (16 degrees C). Eight to 18 weeks later, rats were tested in behavioural measures of anxiety (social interaction and emergence tests), a test of cognition (object recognition test) and the forced swim test of depression. At the conclusion of behavioural testing the rats were killed and their brains analysed using HPLC. MDMA treatment caused a clear and consistent hyperthermia at 28 degrees C and hypothermia at 16 degrees C. Months later, rats pre-treated with MDMA at either 16 or 28 degrees C displayed increased anxiety in the social interaction and emergence tests and reduced escape attempts and increased immobility in the forced swim test. MDMA pre-treatment was also associated with poorer memory on the object recognition test, but only in rats given the drug at 28 degrees C. Rats pre-treated with MDMA showed loss of 5-HT in the hippoc us, striatum, amygdala and cortex, regardless of body temperature at the time of dosing. However, 5-HIAA loss in the amygdala and hippoc us was greater in rats pre-treated at 28 degrees C. Dopamine in the striatum was also depleted in rats given MDMA. These results indicate that hyperthermia at the time of dosing with MDMA is not necessary to produce subsequent 5-HT depletion and anxiety in rats. They also extend previous findings of long-term effects of brief exposure to MDMA in rats to include apparent "depressive" symptoms in the forced swim model.

Parameters That Affect Fear Responses in Rodents and How to Use Them for Management

Publisher: Frontiers Media SA

Date: 08-05-2019

DOI: 10.3389/FEVO.2019.00136

Involvement of hypothalamic peptides in the anorectic action of the CB receptor antagonist rimonabant (SR 141716).

Publisher: Wiley

Date: 06-2009

DOI: 10.1111/J.1460-9568.2009.06750.X

Abstract: Numerous studies have demonstrated that administration of rimonabant (SR 141716), a CB(1) receptor antagonist, causes a decrease in energy intake. However, the mechanisms by which rimonabant exerts its anorectic actions are unclear. The main focus of the study reported here was to establish the chemical identity of neurons that may subserve the anorectic effects of rimonabant. As such three approaches were utilised: (i) the identification of rimonabant-activated neurons using Fos as a marker of neuronal activity (ii) the identification of the chemical phenotype of rimonabant-activated neurons by combining immunocytochemical identification of Fos and feeding-related peptides and (iii) the evaluation of the effect of rimonabant on messenger RNA (mRNA) and protein for a number of feeding-related peptides. Rimonabant-induced Fos-positive nuclei were localized within a range of discrete hypothalamic regions with a predominance in the parvocellular part of the paraventricular nucleus of the hypothalamus, dorsomedial hypothalamus, arcuate nucleus and lateral hypothalamic area. Furthermore, Fos labelling within these hypothalamic regions was colocalized with anorexigenic and orexigenic peptides including melanin-concentrating hormone (MCH), orexin, cocaine- and hetamine-regulated transcript (CART) and alpha-melanocyte-stimulating hormone (alpha-MSH). Rimonabant specifically induced a decrease in NPY and an increase in CART and alpha-MSH mRNA and protein, consistent with its effect in reducing food intake and increasing energy expenditure. As such these data provide insights into the mechanisms of action that may underpin rimonabant's effects on energy balance and body weight.

Preliminary evidence for lowered basal cortisol in a naturalistic sample of methamphetamine polydrug users.

Publisher: American Psychological Association (APA)

Date: 12-2012

DOI: 10.1037/A0029976

Abstract: The effects of chronic meth hetamine use on neuroendocrine functioning in humans are largely undocumented. Here we assessed basal plasma oxytocin, arginine vasopressin, and cortisol levels in a naturalistic s le of meth hetamine polydrug users (n = 12) compared with controls matched for age, gender, education, occupation status, and marital status (n = 17). All of the meth hetamine users tested positive for blood meth hetamine and/or its main metabolite, hetamine. Other drugs of abuse were detected in a small number of meth hetamine users (MDMA [3,4-methylenedioxy-N-methyl hetamine n = 2], THC [delta-9-tetrahydrocannabinol n = 2]). Almost half of the meth hetamine users reported using meth hetamine intravenously, and others smoked or ingested the drug. Meth hetamine users had significantly lower basal plasma cortisol (p = .025), but similar basal plasma oxytocin and arginine vasopressin levels compared with controls. Basal plasma oxytocin was positively correlated (p = .011), with basal plasma arginine vasopressin in controls, but not in meth hetamine users. Meth hetamine users reported higher rates of psychiatric symptoms including substance use disorders, impulsivity, and positive, negative, manic, and disorientation symptoms compared with controls. Psychiatric symptoms were not related to neuroendocrine functioning in either group. These results provide preliminary evidence for lowered basal cortisol levels in meth hetamine polydrug users and encourage further research in to the effects of meth hetamine on neuroendocrine functioning in humans using more highly controlled experimental research designs.

Antidepressants and adolescent brain development

Publisher: Future Medicine Ltd

Date: 11-2011

DOI: 10.2217/FNL.11.51

Abstract: Despite being a first-line treatment for adolescent depression and anxiety, antidepressant drugs appear to have questionable efficacy and carry an increased risk of adverse effects in this population. The neural mechanisms underlying this phenomenon are currently unknown. Recent research into the neural effects of alcohol and recreational drugs suggests that the developmental trajectory of the adolescent brain may be particularly vulnerable to pharmacological disturbance. It is therefore important to consider whether prescription psychotropic drugs may have analogous effects. This article reviews the contribution of recent preclinical, clinical and pharmacogenetic literature to current knowledge on the short-term and enduring neural effects of antidepressants on the adolescent brain, with a particular focus on the major neurotransmitter systems and neuroplasticity.

Detection of Δ⁹ THC in oral fluid following vaporized cannabis with varied cannabidiol (CBD) content: An evaluation of two point‐of‐collection testing devices

Publisher: Wiley

Date: 10-09-2019

DOI: 10.1002/DTA.2687

Paraventricular hypothalamic CB1 cannabinoid receptors are involved in the feeding stimulatory effects of Δ⁹- tetrahydrocannabinol

Publisher: Elsevier BV

Date: 12-2005

DOI: 10.1016/J.NEUROPHARM.2005.03.025

Abstract: The paraventricular nucleus of the hypothalamus (PVN) is the target of converging orexigenic and anorexigenic pathways originating from various hypothalamic sites and is, therefore, considered to be the chief site mediating hypothalamic regulation of energy homeostasis. Although a large body of evidence suggests that central CB(1) cannabinoid receptors mediate food intake, it is not clear whether PVN CB(1) receptors are involved in the control of feeding behaviour. The present study therefore examined the effects of intra-PVN administration of Delta(9)-tetrahydrocannabinol (THC) and the cannabinoid receptor antagonist SR 141716 on feeding. After being habituated to the test environment and injection procedure, sated rats were injected with SR 141716 (0.03-3.0 microg, Experiment 1) alone or in combination with THC (5.0 microg, Experiment 2) into the PVN. Food intake and locomotor activity then were recorded for 120 min. Intra-PVN administration of THC produced a significant increase in food intake that was attenuated by SR 141716. Administration of SR 141716 alone did not affect feeding. Locomotor activity was not significantly affected by any drug treatments, suggesting that effects on feeding were not due to a non-specific reduction in motivated behaviour. These findings suggest an important role for PVN cannabinoid signalling in mediating THC-induced feeding behaviour. These results also demonstrate that the blockade of PVN CB(1) receptors alone is insufficient to reduce baseline feeding behaviour under these conditions.

Intermittent access to beer promotes binge-like drinking in adolescent but not adult Wistar rats

Publisher: Elsevier BV

Date: 06-2009

DOI: 10.1016/J.ALCOHOL.2009.02.005

Abstract: Teenagers are more likely than adults to engage in binge drinking and could be more vulnerable to long-term brain changes following alcohol abuse. We investigated the possibility of excessive adolescent drinking in a rodent model in which beer (4.44% ethanol vol/vol) is presented to adult and adolescent male Wistar rats. Experiment 1 tracked ad libitum beer and water consumption in group-housed rats from postnatal day (PND) 28-96. Rats consumed an average of 7.8 g/kg/day of ethanol during adolescence (PND 34-55) and this gradually declined to a lower level of intake in adulthood (PND 56-93) of 3.9 g/kg/day. In Experiment 2, beer was made available to both adolescent (PND 29+) and adult (PND 57+) rats for 2h each day in a custom-built "lickometer" apparatus over 75 days. Access to beer was provided either 1 day out of every 3 ("intermittent" groups) or every day ("daily" groups). Relative to body weight, adolescent rats consumed more beer than adult rats in these limited access sessions. Adolescents with intermittent access consumed more than adolescents with daily access, a "binge"-like effect that was not observed in adult groups and that disappeared in adulthood. After 3 months of daily or intermittent alcohol consumption, the preference for beer versus sucrose was assessed. Rats previously kept under an intermittent schedule displayed a higher preference for beer relative to 3% sucrose, but only when testing occurred after 2 days of abstinence. In Experiment 3, adolescent (PND 30-37) and adult (PND 58-65) rats were given 20-min access to beer and their blood alcohol concentrations (BACs) were assessed. Adolescent groups consumed more alcohol than adults and showed higher BACS that were typical of human "binge" drinking (>80 mg/dL). Despite this, the correlation between BAC and beer intake was similar in both age groups. Together these results show that the intermittent presentation of alcohol itself appears to have subtle long-lasting effects on the motivation to consume alcohol. The findings support the use of beer solutions in modeling binge-like patterns of human alcohol consumption in adolescent rats.

Metabolomics of Neurotransmitters and Related Metabolites in Post-Mortem Tissue from the Dorsal and Ventral Striatum of Alcoholic Human Brain

Publisher: Springer Science and Business Media LLC

Date: 22-01-2016

DOI: 10.1007/S11064-016-1830-3

Abstract: We report on changes in neurotransmitter metabolome and protein expression in the striatum of humans exposed to heavy long-term consumption of alcohol. Extracts from post mortem striatal tissue (dorsal striatum DS comprising caudate nucleus CN and putamen P and ventral striatum VS constituted by nucleus accumbens NAc) were analysed by high performance liquid chromatography coupled with tandem mass spectrometry. Proteomics was studied in CN by two-dimensional gel electrophoresis followed by mass-spectrometry. Proteomics identified 25 unique molecules expressed differently by the alcohol-affected tissue. Two were dopamine-related proteins and one a GABA-synthesizing enzyme GAD65. Two proteins that are related to apoptosis and/or neuronal loss (BiD and amyloid-β A4 precursor protein-binding family B member 3) were increased. There were no differences in the levels of dopamine (DA), 3,4-dihydrophenylacetic acid (DOPAC), serotonin (5HT), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (HIAA), histamine, L-glutamate (Glu), γ-aminobutyric acid (GABA), tyrosine (Tyr) and tryptophan (Tryp) between the DS (CN and P) and VS (NAc) in control brains. Choline (Ch) and acetylcholine (Ach) were higher and norepinephrine (NE) lower, in the VS. Alcoholic striata had lower levels of neurotransmitters except for Glu (30 % higher in the alcoholic ventral striatum). Ratios of DOPAC/DA and HIAA/5HT were higher in alcoholic striatum indicating an increase in the DA and 5HT turnover. Glutathione was significantly reduced in all three regions of alcohol-affected striatum. We conclude that neurotransmitter systems in both the DS (CN and P) and the VS (NAc) were significantly influenced by long-term heavy alcohol intake associated with alcoholism.

Cannabinoids, Insomnia, and Other Sleep Disorders

Publisher: Elsevier BV

Date: 08-2022

DOI: 10.1016/J.CHEST.2022.04.151

Abstract: Sleep disturbances are often cited as a primary reason for medicinal cannabis use, and there is increasing clinical interest in the therapeutic potential of cannabinoids in treating sleep disorders. Burgeoning evidence suggests a role of the endocannabinoid system in regulating the circadian sleep-wake cycle, highlighting a potential avenue for developing novel therapeutics. Despite widespread use of cannabis products as sleep aids globally, robustly designed studies verifying efficacy in sleep-disordered populations are limited. Although some study outcomes have suggested cannabinoid utility in insomnia disorder and sleep apnea, most studies to date are limited by small s le sizes, lack of rigorously controlled study designs, and high risk of bias. This critical review summarizes the current evidence for the use of cannabinoids as a treatment for sleep disorders and provides an overview of endocannabinoid modulation of sleep-wake cycles, as well as the sleep-modulating effects of plant-derived cannabinoids such as delta-9-tetrahydrocannbinol, cannabidiol, and cannabinol. The review also discusses practical considerations for clinicians regarding cannabinoid formulations, routes of administration, respiratory concerns, dosing, potential side effects, drug interactions, and effects relevant to driving, tolerance, and withdrawal. Although current interest in, and uptake of, medicinal cannabis use for sleep disorders may have surpassed the evidence base, there is a strong rationale for continued investigation into the therapeutic potential of cannabinoids.

Intravenous methamphetamine self-administration in rats: Effects of intravenous or intraperitoneal MDMA co-administration

Publisher: Elsevier BV

Date: 10-2018

DOI: 10.1016/J.PBB.2006.09.015

Abstract: The combined use of 3,4-methylenedioxymeth hetamine (MDMA, 'Ecstasy') with meth hetamine (METH) by recreational drug users is of particular concern due to their similar pharmacological and toxic profiles. In the current study we sought to elucidate why combining these particular drugs is such a popular choice among party-drug users. This was investigated through characterisation of the possible interactive effects of MDMA on METH intravenous self-administration. The first experiment involved characterisation of the METH dose-response curve for intravenous self-administration. Male Hooded-Wistar rats were trained to self-administer intravenous METH (0.01-0.3 mg/kg/infusion) and an inverted-U dose-response curve was obtained. In Experiment 2, a second squad of rats self-administered 0.01, 0.03 or 0.1 mg/kg/infusion METH and had small amounts of MDMA (0.001-0.03 mg/kg) then introduced into the infusion solution. Addition of MDMA to the METH infusion solution resulted in a dose independent reduction in responding. In Experiment 3, a third squad of rats was treated 20 min pre-session with an intraperitoneal injection of saline, 1.25 or 2.5 mg/kg of MDMA or METH to evaluate whether the reduction in responding evident in Experiment 2 was due to an MDMA-induced decrease in locomotor activity. Pre-treatment with intraperitoneal MDMA or METH had no effect on METH self-administration nor activity. We hypothesise that the reduction in METH self-administration caused by MDMA may reflect inhibitory effects of MDMA-induced 5-HT release on dopaminergic mechanisms.

Protein expression profile in the striatum of acute methamphetamine-treated rats

Publisher: Elsevier BV

Date: 06-2006

DOI: 10.1016/J.BRAINRES.2006.04.052

Abstract: Meth hetamine (MAP) is an addictive drug with psychostimulant effects. It is known that MAP induces behavioral changes, including hyperlocomotion and stereotypical movements in rodents. These behavioral changes induced by MAP have been compared with behavioral changes in patients with MAP addiction and MAP psychosis. However, little is known about the underlying mechanisms of MAPs effects on global protein expression. 2-DE proteomics allows us to examine global changes in protein expression in complex biological systems and to propose possible hypotheses of the underlying mechanisms in various pathological conditions. In the present study, we aim to identify protein expression profiles in the striatum (ST) of acute low dose MAP (1 mg/kg)-treated rats using 2-DE proteomics. Rats were given an intraperitoneal injection of MAP (1 mg/kg) or saline. Locomotor activity was monitored. Proteins were extracted from the ST of MAP-treated and saline-treated control rats then separated and analyzed using 2-DE. RESULTS. Low dose MAP administration significantly increased locomotor activity. 2-DE analysis revealed 36 protein spots differentially regulated in the ST of acute MAP-treated rats compared to a vehicle-treated control. 26 protein spots have been identified using MALDI-TOF, including phosphoglycerate kinase 1, Dihydrolipoamide dehydrogenase, Voltage-dependent anion-selective channel protein 1, Rho GDP dissociation inhibitor alpha, peroxiredoxin 2, ubiquitin carboxy-terminal hydrolase L1, and actin beta, N-tropomodulin. These proteins could be related to underlying mechanisms of acute low dose MAP effects, indicating mitochondrial dysfunction, oxidative damages, lysosomal degradation, degenerative processes, and neuronal modification.

Oxytocin and MDMA ('Ecstasy') enhance social reward in rats

Publisher: Springer Science and Business Media LLC

Date: 15-03-2015

DOI: 10.1007/S00213-015-3899-9

Abstract: Oxytocin (OT), vasopressin (AVP) and 3,4 methylenedioxymeth hetamine (MDMA, 'Ecstasy') all increase social interaction in rats, perhaps by enhancing the rewarding value of social encounters. Here, we used the conditioned place preference (CPP) paradigm to assess the intrinsic rewarding effects of OT, AVP and MDMA, and whether these effects are enhanced by the presence of a conspecific, or a dynamic, tactile object (a tennis ball). Adult male rats received conditioning sessions in a CPP apparatus twice a day (vehicle at 10 a.m., drug at 3 p.m.). Experiment 1 involved conditioning with OT (0.5 mg/kg, intraperitoneal (i.p.)), AVP (0.005 mg/kg, i.p.) or MDMA (5 mg/kg, i.p.). Experiments 2 and 3 involved conditioning with the same treatments but in the presence of a conspecific receiving the same treatment (social-CPP) or in the presence of a tennis ball (object-CPP), respectively. Conditioned place preference was assessed 24 h, 2 weeks and 4 weeks later. OT, AVP and MDMA did not produce a conventional CPP. However, when the conditioning environment also contained a conspecific both OT and MDMA induced a significant CPP lasting for at least 4 weeks. Rats given OT and MDMA also developed a more modest yet significant CPP for the environment where they encountered a tennis ball. These results indicate that OT and MDMA can augment the rewarding effects of social interaction, but also interaction with a dynamic and tactile non-social object. AVP does not condition social- or object-CPPs and may promote social proximity by inducing generalized anxiety and defensive aggregation.

Repeated exposure to ?⁹-tetrahydrocannabinol alters heroin-induced locomotor sensitisation and Fos-immunoreactivity

Publisher: Elsevier BV

Date: 12-2005

DOI: 10.1016/J.NEUROPHARM.2005.07.008

Abstract: The present study examined the effect of chronic exposure to Delta(9)-tetrahydrocannabinol (THC) on heroin-induced locomotor sensitisation and Fos-immunoreactivity (Fos-IR). Adult male albino Wistar rats (n=60) were injected intraperitoneally (i.p.) 21 times with vehicle, 0.05, 0.5, or 5.0mg/kg THC (once every 48 h for 41 days). Locomotor activity was assessed for 180 min on pre-exposure days 1, 21, and 41. Following a 2-week washout period, rats were ided into five equal groups (n=12) and injected subcutaneously (s.c.) with vehicle or heroin (0.5mg/kg). Locomotor activity was recorded for 240 min. In drug-naïve rats, heroin significantly increased locomotor activity. THC pre-exposure further increased heroin-induced locomotion. After an interval of 2 weeks, rats pre-exposed to vehicle and 5.0mg/kg THC in the first part of the experiment were randomly assigned to one of four treatment groups (n=6) and injected s.c. with vehicle or 0.5mg/kg heroin and perfused 2h later. Fos-IR was examined in several brain regions. Acute heroin increased Fos-IR in drug-naïve rats in the caudate-putamen (CPu central, medial and dorsomedial regions), nucleus accumbens (NAC core and shell regions), bed nucleus of the stria terminalis (BNST), lateral septum, central nucleus of the amygdala (CEA), periaqueductal grey (PAG dorsolateral, dorsomedial, and lateral), and the Edinger-Westphal nucleus. Pre-exposure to THC significantly increased heroin-induced Fos-IR in the dorsomedial CPu and the NAC (core). Conversely, THC pre-exposure reduced heroin-induced Fos-IR in the BNST, CEA, and the PAG (dorsolateral and lateral). The present study demonstrates that THC pre-exposure increases the locomotor stimulating effects of heroin and provides new evidence for the neural correlates that may underlie cannabinoid and opioid cross-sensitisation.

Adolescent pre-treatment with oxytocin protects against adult methamphetamine-seeking behavior in female rats

Publisher: Wiley

Date: 17-11-2016

DOI: 10.1111/ADB.12197

Abstract: The neuropeptide oxytocin (OT), given acutely, reduces self-administration of the psychostimulant drug meth hetamine (METH). Additionally, chronic OT administration to adolescent rats reduces levels of alcohol consumption in adulthood, suggesting developmental neuroplasticity in the OT system relevant to addiction-related behaviors. Here, we examined whether OT exposure during adolescence might subsequently inhibit METH self-administration in adulthood. Female Sprague-Dawley rats were administered vehicle or OT (1 mg/kg, i.p.) once daily from postnatal days (PND) 28 to 37 (adolescence). At PND 62 (adulthood), rats were trained to self-administer METH (intravenous, i.v.) in daily 2-hour sessions for 10 days under a fixed ratio 1 (FR1) reinforcement schedule, followed by determination of dose-response functions (0.01-0.3 mg/kg/infusion, i.v.) under both FR1 and progressive ratio (PR) schedules of reinforcement. Responding was then extinguished, and relapse to METH-seeking behavior assessed following priming doses of non-contingent METH (0.1-1 mg/kg, i.p.). Finally, plasma was collected to determine pre-treatment effects on OT and corticosterone levels. Results showed that OT pre-treatment did not significantly inhibit the acquisition of METH self-administration or FR1 responding. However, rats pre-treated with OT responded significantly less for METH under a PR reinforcement schedule, and showed reduced METH-primed reinstatement with the 1 mg/kg prime. Plasma OT levels were also significantly higher in OT pre-treated rats. These results confirm earlier observations that adolescent OT exposure can subtly, yet significantly, inhibit addiction-relevant behaviors in adulthood.

Pharmacology of Cumyl-Carboxamide Synthetic Cannabinoid New Psychoactive Substances (NPS) CUMYL-BICA, CUMYL-PICA, CUMYL-5F-PICA, CUMYL-5F-PINACA, and Their Analogues

Publisher: American Chemical Society (ACS)

Date: 11-08-2017

DOI: 10.1021/ACSCHEMNEURO.7B00267

Abstract: Synthetic cannabinoids (SC) are the largest class of new psychoactive substances (NPS), and are increasingly associated with serious adverse effects. The majority of SC NPS are 1,3-disubstituted indoles and indazoles featuring a ersity of subunits at the 1- and 3-positions. Most recently, cumyl-derived indole- and indazole-3-carboxamides have been detected by law enforcement agencies and by emergency departments. Herein we describe the synthesis, characterization, and pharmacology of SCs CUMYL-BICA, CUMYL-PICA, CUMYL-5F-PICA, CUMYL-PINACA, CUMYL-5F-PINACA, and related analogues. All cumyl-derived SCs were potent, efficacious agonists at CB

Hippocampal protein expression is differentially affected by chronic paroxetine treatment in adolescent and adult rats: a possible mechanism of “paradoxical” antidepressant responses in young persons

Publisher: Frontiers Media SA

Date: 2013

DOI: 10.3389/FPHAR.2013.00086

WAY 267,464, a non-peptide oxytocin receptor agonist, impairs social recognition memory in rats through a vasopressin 1A receptor antagonist action

Publisher: Springer Science and Business Media LLC

Date: 13-03-2015

DOI: 10.1007/S00213-015-3902-5

Abstract: Recent in vitro studies suggest that the oxytocin receptor (OTR) agonist WAY 267,464 has vasopressin 1A receptor (V1AR) antagonist effects. This might limit its therapeutic potential due to the positive involvement of the V1AR in social behavior. The objective of this study was to assess functional V1AR antagonist-like effects of WAY 267,464 in vivo using a test of social recognition memory. Adult experimental rats were tested for their recognition of a juvenile conspecific rat that they had briefly met 30 or 120 min previously. The modulatory effects of vasopressin (AVP), the selective V1AR antagonist SR49059, and WAY 267,464 were examined together with those of the selective OTR antagonist Compound 25 (C25). Drugs were administered immediately after the first meeting. Control rats showed recognition of juveniles at a 30 min, but not a 120 min retention interval. AVP (0.005, but not 0.001 mg/kg intraperitoneal (i.p.)) improved memory such that recognition was evident after 120 min. This was prevented by pretreatment with SR49059 (1 mg/kg) and WAY 267,464 (10, 30, and 100 mg/kg). Given alone, SR49059 (1 mg/kg) and WAY 267,464 (30 and 100 mg/kg) impaired memory at a 30 min retention interval. The impairment with WAY 267,464 was not prevented by C25 (5 mg/kg), suggesting V1AR rather than OTR mediation of the effect. Given alone, C25 also impaired memory. These results highlight a tonic role for endogenous AVP (and oxytocin) in social recognition memory and indicate that WAY 267,464 functions in vivo as a V1AR antagonist to prevent the memory-enhancing effects of AVP.

Increased anxiety 3 months after brief exposure to MDMA ('Ecstasy') in rats: Association with altered 5-HT transporter and receptor density

Publisher: Springer Science and Business Media LLC

Date: 26-02-2003

DOI: 10.1038/SJ.NPP.1300185

Cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC) for chronic insomnia disorder (‘CANSLEEP’ trial): protocol for a randomised, placebo-controlled, double-blinded, proof-of-concept trial

Publisher: BMJ

Date: 05-2020

DOI: 10.1136/BMJOPEN-2019-034421

Abstract: Insomnia is a highly prevalent and costly condition that is associated with increased health risks and healthcare utilisation. Anecdotally, cannabis use is frequently reported by consumers to promote sleep. However, there is limited research on the effects of cannabis on sleep and daytime function in people with insomnia disorder using objective measures. This proof-of-concept study will evaluate the effects of a single dose of an oral cannabis-based medicine on sleep and daytime function in participants with chronic insomnia disorder. A randomised, crossover, placebo-controlled, single-dose study design will be used to test the safety and efficacy of an oral oil solution (‘ETC120’) containing 10 mg Δ 9 -tetrahydrocannabinol (THC) and 200 mg cannabidiol (CBD) in 20 participants diagnosed with chronic insomnia disorder. Participants aged 35–60 years will be recruited over an 18-month period commencing August 2019. Each participant will receive both the active drug and matched placebo, in a counterbalanced order, during two overnight study assessment visits, with at least a 1-week washout period between each visit. The primary outcomes are total sleep time and wake after sleep onset assessed via polysomnography. In addition, 256-channel high-density electroencephalography and source modelling using structural brain MRI will be used to comprehensively examine brain activation during sleep and wake periods on ETC120 versus placebo. Next-day cognitive function, alertness and simulated driving performance will also be investigated. Ethics approval was received from Bellberry Human Research Ethics Committee (2018-04-284). The findings will be disseminated in a peer-reviewed open-access journal and at academic conferences. ANZCTRN12619000714189.

The cannabinoid receptor antagonist SR 141716 attenuates overfeeding induced by systemic or intracranial morphine

Publisher: Springer Science and Business Media LLC

Date: 07-2003

DOI: 10.1007/S00213-003-1451-9

Abstract: Considerable interplay exists between the brain's opioid and cannabinoid systems. These systems are both involved in the control of appetite and research supports the notion that the opioid system modulates the role of the cannabinoid system on appetite. However, the ability of the cannabinoid system to modulate the opioid system's control over appetite has not been well studied. The present study examined the role of cannabinoid CB(1) receptors in the control of opioid-induced feeding, and sought to identify specific brain regions underlying this role. After being habituated to the test environment and injection procedure, sated rats were injected with the cannabinoid CB(1) receptor antagonist SR 141716 (0.03-3.0 mg/kg, IP). Thirty minutes later, morphine or its vehicle were administered systemically (2.5 mg/kg SC, experiments 1 and 2) or intracranially into the nucleus accumbens (nAcc, experiment 3) or paraventricular nucleus of the hypothalamus (PVN, experiment 4). Food intake and locomotor activity was then recorded for 120 min. A significant increase in food intake was observed following systemic and intracranial (10 nmol) application of morphine in all experiments. SR 141716 suppressed systemic and intra-PVN morphine induced feeding (experiments 2 and 4), but did not attenuate food intake induced by intra-nAcc application of morphine (experiment 3). Because SR 141716 had no effect on intra-nAcc morphine-stimulated feeding, it would appear that cannabinoid receptors do not modify opioid-mediated hedonic responses to food. Rather, we conclude that cannabinoid CB(1) receptor blockade may suppress opioid-induced feeding by stimulating the release of satiety-related peptides within the hypothalamus. Further, because SR 141716 did not block morphine induced locomotor activity, the observed effects on feeding do not appear to be due to a non-specific reduction in motivated behaviour.

Double deficiency of toll-like receptors 2 and 4 alters long-term neurological sequelae in mice cured of pneumococcal meningitis

Publisher: Springer Science and Business Media LLC

Date: 07-11-2019

DOI: 10.1038/S41598-019-52212-7

Abstract: Toll-like receptor (TLR) 2 and 4 signalling pathways are central to the body’s defence against invading pathogens during pneumococcal meningitis. Whereas several studies support their importance in innate immunity, thereby preventing host mortality, any role in protecting neurological function during meningeal infection is ill-understood. Here we investigated both the acute immunological reaction and the long-term neurobehavioural consequences of experimental pneumococcal meningitis in mice lacking both TLR2 and TLR4. The absence of these TLRs significantly impaired survival in mice inoculated intracerebroventricularly with Streptococcus pneumoniae . During the acute phase of infection, TLR2/4-deficient mice had lower cerebrospinal fluid concentrations of interleukin-1β, and higher interferon-γ, than their wild-type counterparts. After antibiotic cure, TLR2/4 double deficiency was associated with aggravation of behavioural impairment in mice, as shown by diurnal hypolocomotion throughout the adaptation phases in the Intellicage of TLR-deficient mice compared to their wild-type counterparts. While TLR2/4 double deficiency did not affect the cognitive ability of mice in a patrolling task, it aggravated the impairment of cognitive flexibility. We conclude that TLR2 and TLR4 are central to regulating the host inflammatory response in pneumococcal meningitis, which may mediate erse compensatory mechanisms that protect the host not only against mortality but also long-term neurological complications.

A long hangover from party drugs: Residual proteomic changes in the hippocampus of rats 8 weeks after γ-hydroxybutyrate (GHB), 3,4-methylenedioxymethamphetamine (MDMA) or their combination

Publisher: Elsevier BV

Date: 07-2010

DOI: 10.1016/J.NEUINT.2010.03.002

Abstract: 3,4-Methylenedioxymeth hetamine (MDMA) and gamma-hydroxybutyrate (GHB) are popular party drugs that are used for their euphoric and prosocial effects, and sometimes in combination. Both drugs increase markers of oxidative stress in the hippoc us and can cause lasting impairments in hippoc al-dependent forms of memory. To gain further information on the biochemical mechanisms underlying these effects, the current study examined residual changes in hippoc al protein expression measured 8 weeks after chronic administration of GHB (500mg/kg), MDMA (5mg/kg) or their combination (GHB/MDMA). The drugs were administered once a day for 10 days in an environment with an elevated ambient temperature of 28 degrees C. Results showed significant changes in protein expression, relative to controls, in all three groups: MDMA and GHB given alone caused residual changes in 8 and 5 proteins respectively, while the GHB/MDMA combination significantly changed 6 proteins. The altered proteins had roles in neuroplasticity, neuroprotection, intracellular signalling and cytoskeletal function. The largest change (-4.3-fold) was seen in the MDMA group with the protein C-crk: a protein implicated in learning-related neuroplasticity. The second largest change (3.0-fold) was seen in the GHB group in Glutathione-S-transferase (GST), a protein that protects against oxidative stress. Two cytoskeletal proteins (Tubulin Folding Cofactor B and Tropomyosin-alpha-3 chain) and one plasticity related protein (Neuronal Pentraxin-1 NP1) were similarly changed in both the MDMA and the GHB groups, while two intracellular signalling proteins (alpha-soluble NSF-attachment protein and subunits of the V-type proton ATPase) were changed in both the MDMA/GHB and the MDMA groups. These results provide some insight into the molecular pathways possibly underlying the lasting cognitive deficits arising from GHB and/or MDMA use.

Urinary cannabinoid levels during nabiximols (Sativex®)-medicated inpatient cannabis withdrawal

Publisher: Springer Science and Business Media LLC

Date: 04-08-2017

DOI: 10.1007/S11419-016-0330-0

Preexposure to MDMA (Ecstasy) delays acquisition but facilitates MDMA-induced reinstatement of amphetamine self-administration behavior in rats

Publisher: Elsevier BV

Date: 10-2004

DOI: 10.1016/J.PBB.2004.08.004

Abstract: The current experiment investigated the effect of 3,4-methylenedioxymeth hetamine (MDMA 'Ecstasy') preexposure on the acquisition of intravenous hetamine self-administration and the reinstatement of hetamine-seeking behavior by either MDMA or hetamine. Rats were preexposed to a 5-HT depleting regime of MDMA (5 mg/kg every hour for 4 h on two consecutive days) or equivalent vehicle injections. Intravenous self-administration of low dose d- hetamine (0.03 mg/kg/infusion) on a FR1 schedule was subsequently assessed. The rats were then given 2 weeks of extinction and tested for drug-seeking behavior with priming doses of hetamine or MDMA. Brains were analysed for monoamine content using high-performance liquid chromatography (HPLC). MDMA-preexposed rats were initially slower to acquire hetamine self-administration. However, by day 6 of acquisition, there was no difference from controls. Following extinction, hetamine (1 mg/kg, i.p.) reinstated drug seeking and produced locomotor hyperactivity in both MDMA- and vehicle-pretreated animals. However, MDMA (5 mg/kg, i.p.) was only effective in producing hetamine seeking and hyperactivity in MDMA-pretreated rats. MDMA pretreatment caused significant decreases in 5-hydroxy-indolacetic acid (5-HIAA) and 5-HT in several brain regions. These results suggest that 5-HT depletion induced by MDMA may initially slow the acquisition of hetamine self-administration but that MDMA preexposure may also sensitize animals to the locomotor stimulating and priming effects of MDMA on drug-seeking behavior.

Access to cannabidiol without a prescription: A cross-country comparison and analysis

Publisher: Elsevier BV

Date: 11-2020

DOI: 10.1016/J.DRUGPO.2020.102935

A cross-sectional survey exploring the knowledge, experiences and attitudes of Australian pharmacists toward medicinal cannabis

Publisher: Springer Science and Business Media LLC

Date: 29-11-2022

DOI: 10.1007/S11096-022-01519-Z

Abstract: Australian pharmacists currently dispense a wide range of prescription-only cannabis-based medicines. Recent regulatory changes will expand the role of pharmacists, allowing certain low-dose cannabidiol products to be supplied without a prescription in pharmacies. This harmonises Australia with many other countries where cannabidiol products are readily available to consumers. To examine Australian pharmacists’ experience, knowledge and attitudes towards medicinal cannabis and their preparedness to supply over-the-counter low-dose cannabidiol products. We conducted a cross-sectional study using a 51-item on-line questionnaire that was informed by previous surveys of health professionals and assessed for face validity. Australian pharmacists were recruited to complete the survey between May and December 2021, primarily through professional pharmacy organisations. Pharmacists were included in the final dataset if they completed the demographic characteristics section and at least one additional section of the questionnaire. Data were analysed using descriptive and relational statistical tests. There were 272 attempts to complete this survey and 217 responses included in the final dataset. Over half of the respondents (60.0%, 130/217) had dispensed at least one medicinal cannabis prescription during their career and 58.5% (127/217) had received at least one medicinal cannabis enquiry in the last fortnight. Only around half (53.9%, 117/217) felt comfortable supplying medicinal cannabis products and fewer (39.3%, 79/201) were confident discussing cannabis-related enquiries. More than half of the respondents (58.7%, 118/201) supported the provision of low-dose cannabidiol products through pharmacies. Two-thirds (67.8%, 80/118) of respondents achieved relatively low scores ( 60%) in the knowledge component of the survey. Most respondents (94.2%, 178/189) endorsed a need for further training in this area. Australian pharmacists tended to support medicinal cannabis availability and improved access to low-dose cannabidiol products via pharmacies. However, results highlight a need for improved training and education of pharmacists around cannabis-based medicines.

TMT-induced autonomic and behavioral changes and the neural basis of its processing

Publisher: Elsevier BV

Date: 2005

DOI: 10.1016/J.NEUBIOREV.2005.04.018

Abstract: One of the main interests in the field of neuroscience is the investigation of the neural basis of fear. During recent years, an increasing number of studies have used trimethylthiazoline (TMT), a component of red fox feces, as a stimulus to induce fear in predator naive rats, mice, and voles. The aim of the present review is to summarize these studies. We present an overview to the autonomic and behavioral changes that are induced by TMT exposure. Then, we summarize the small number of studies that have examined the neural processing of the TMT stimulus. Finally, we compare these studies with those using a natural predator or predator odor to induce fear and discuss the possible use of TMT exposure in rodents as an animal model of unconditioned fear in humans.

The distribution of γ-hydroxybutyrate-induced Fos expression in rat brain: Comparison with baclofen

Publisher: Elsevier BV

Date: 2009

DOI: 10.1016/J.NEUROSCIENCE.2008.10.011

Abstract: gamma-Hydroxybutyrate (GHB) is a euphoric, prosocial and sleep inducing drug that binds with high affinity to its own GHB receptor site and also more weakly to GABA(B) receptors. GHB is efficacious in the treatment of narcolepsy and alcoholism, but heavy use can lead to dependence and withdrawal. Many effects of GHB (sedation, hypothermia, catalepsy) are mimicked by GABA(B) receptor agonists (e.g. baclofen). However other effects (euphoric and prosocial effects and a therapeutic effect in narcolepsy) are not. The present study used Fos immunohistochemistry to assess the neural activation produced in rat brain by medium to high doses of GHB (250, 500 and 1000 mg/kg) and a high dose of baclofen (10 mg/kg) that produced similar sedation to 500 mg/kg GHB. Results showed many common regions of activation with these two drugs including the supraoptic, paraventricular, median preoptic and ventral premammillary nuclei of the hypothalamus, the central nucleus of the amygdala, Edinger-Westphal nucleus, lateral parabrachial nucleus, locus coeruleus, and nucleus of the solitary tract. GHB (500 mg/kg), but not baclofen (10 mg/kg), induced significant Fos expression in the median raphe nucleus and lateral habenula, while a higher dose of GHB (1000 mg/kg) induced additional Fos expression in the islands of Calleja, dentate gyrus (polymorphic layer) and arcuate nucleus, and in various regions implicated in rapid and non-rapid eye movement sleep (laterodorsal tegmental nucleus, tuberomammillary nucleus and the ventrolateral and anterodorsal preoptic nuclei). Surprisingly, Fos immunoreactivity was not observed with either GHB or baclofen in reward-relevant regions such as the nucleus accumbens, striatum and ventral tegmental area. Overall these results indicate a distinctive signature of brain activation with GHB that may be only partly due to GABA(B) receptor effects. This confirms a unique neuropharmacological profile for GHB and indicates key neural substrates that may underlie its characteristic influence on sleep, body temperature, sociability and endocrine function.

Structure–activity relationships of synthetic cannabinoid designer drug RCS-4 and its regioisomers and C4 homologues

Publisher: Springer Science and Business Media LLC

Date: 31-05-2015

DOI: 10.1007/S11419-015-0282-9

Oxytocin decreases methamphetamine self-administration, methamphetamine hyperactivity, and relapse to methamphetamine-seeking behaviour in rats.

Publisher: Elsevier BV

Date: 2010

DOI: 10.1016/J.NEUROPHARM.2009.06.018

Abstract: There is emerging evidence that the neuropeptide oxytocin may be utilised as a treatment for various psychopathologies, including drug addictions. Here we used an animal model to assess whether oxytocin might be effective in the treatment of meth hetamine addiction. Sprague-Dawley rats were trained to lever press to intravenously self-administer meth hetamine under a progressive ratio schedule of reinforcement. Once responding had stabilised, one group of rats received escalating doses of oxytocin (0.001, 0.01, 0.1, 0.3, 1 mg/kg) administered intraperitoneally (IP) prior to daily self-administration tests, while other rats received vehicle. After these tests, lever-pressing was extinguished and the ability of meth hetamine primes (IP, 1 mg/kg) to reinstate responding was studied with and without co-administration of oxytocin (IP, 0.3 and 1 mg/kg). Results showed that oxytocin dose-dependently reduced responding for intravenous meth hetamine with an almost complete absence of responding at the highest oxytocin dose (1 mg/kg). Hyperactivity during meth hetamine self-administration was also dose-dependently reduced by oxytocin. Oxytocin (1 but not 0.3 mg/kg) also reduced the ability of meth hetamine to reinstate meth hetamine-seeking behaviour. In separate tests, oxytocin (IP, 0.3 and 1 mg/kg) robustly decreased the hyperactivity and rearing induced by meth hetamine challenge (IP, 1 mg/kg), producing activity levels similar to control animals. This study suggests that oxytocin may have a powerful inhibitory effect on the motivation to consume meth hetamine and on hyperactivity associated with acute meth hetamine intoxication. These results point to the potential utility of human trials of oxytocin as a therapeutic treatment for meth hetamine addiction.

Give me a hi-5! An additional version of the h-index

Publisher: SAGE Publications

Date: 26-11-2013

DOI: 10.1177/0004867413513506

Composition and use of cannabis extracts for childhood epilepsy in the australian community

Publisher: Springer Science and Business Media LLC

Date: 05-07-2018

DOI: 10.1038/S41598-018-28127-0

Abstract: Recent surveys suggest that many parents are using illicit cannabis extracts in the hope of managing seizures in their children with epilepsy. In the current Australian study we conducted semi-structured interviews with families of children with erse forms of epilepsy to explore their attitudes towards and experiences with using cannabis extracts. This included current or previous users of cannabis extracts to treat their child’s seizures (n = 41 families), and families who had never used (n = 24 families). For those using cannabis, extracts were analysed for cannabinoid content, with specific comparison of s les rated by families as “effective” versus those rated “ineffective”. Results showed that children given cannabis extracts tended to have more severe epilepsy historically and had trialled more anticonvulsants than those who had never received cannabis extracts. There was high variability in the cannabinoid content and profile of cannabis extracts rated as “effective”, with no clear differences between extracts perceived as “effective” and “ineffective”. Contrary to family’s expectations, most s les contained low concentrations of cannabidiol, while Δ 9 -tetrahydrocannabinol was present in nearly every s le. These findings highlight profound variation in the illicit cannabis extracts being currently used in Australia and warrant further investigations into the therapeutic value of cannabinoids in epilepsy.

The First CNS-Active Carborane: A Novel P2X₇ Receptor Antagonist with Antidepressant Activity

Publisher: American Chemical Society (ACS)

Date: 03-04-2014

DOI: 10.1021/CN500054N

Cannabis reward: Biased towards the fairer sex?

Publisher: Wiley

Date: 11-2007

DOI: 10.1038/SJ.BJP.0707469

Protein expression profile in the striatum of rats with methamphetamine-induced behavioral sensitization

Publisher: Wiley

Date: 04-2007

DOI: 10.1002/PMIC.200600595

Abstract: Repeated administration of meth hetamine (MAP) results in an increased behavioral response to the drug during subsequent exposure. This phenomenon is called behavioral sensitization. Sensitization is an enduring phenomenon, and suggests chronic alterations in neuronal plasticity. MAP-induced sensitization has been proposed and widely investigated as an animal model of MAP psychosis and schizophrenia. However, little is known about the molecular mechanisms underlying MAP-induced sensitization. 2-DE-based proteomics allows us to examine global changes in protein expression in complex biological systems and to propose hypotheses concerning the mechanisms underlying various pathological conditions. In the present study, we examined protein expression profiles in the striatum of MAP-sensitized rats using 2-DE-based proteomics. Repeated administration of MAP (4.0 mg/kg, once a day, intraperitoneal (i.p.)) for 10 days significantly augmented the locomotor response to an MAP challenge injection (1.0 mg/kg, i.p.) on day 11. This enhanced activity was maintained even after a week of drug abstinence. 2-DE analysis revealed 42 protein spots were differentially regulated in the striatum of MAP-sensitized rats compared to control. Thirty-one protein spots were identified using MALDI-TOF, including synapsin II, synaptosomal-associated protein 25 (SNAP-25), adenylyl cyclase-associated protein 1 (CAP1), and dihydropyrimidinase-related protein 2 (DRP2). These proteins can be related to underlying mechanisms of MAP-induced behavioral sensitization, indicating cytoskeletal modification, and altered synaptic function.

Antibody-induced neutrophil depletion prior to the onset of pneumococcal meningitis influences long-term neurological complications in mice

Publisher: Elsevier BV

Date: 08-2016

DOI: 10.1016/J.BBI.2016.01.021

Abstract: During pneumococcal meningitis, clearance of bacteria by recruited neutrophils is crucial for host protection. However, these innate immune mechanisms are often insufficient and treatment with antibiotics is necessary to prevent death. Despite this antibiotic treatment, approximately half of all survivors suffer lifelong neurological problems. There is growing evidence indicating the harmful effects of neutrophils on CNS integrity. Therefore, the present study investigated the roles of neutrophils in the acute inflammatory response and the resulting long-term neuropsychological effects in murine pneumococcal meningitis. Long-term behavioural and cognitive functions in mice were measured using an automated IntelliCage system. Neutrophil depletion with antibody 1A8 as adjunctive therapy was shown to remarkably impair survival in meningitic C57BL/6J mice despite antibiotic (ceftriaxone) treatment. This was accompanied by increased bacterial load in the cerebrospinal fluid (CSF) and an increase in IL-1β, but decrease in TNF, within the CSF at 20h after bacterial inoculation. In the longer term, the surviving neutrophil-depleted post-meningitic (PM) mice displayed reduced diurnal hypolocomotion compared to PM mice treated with an isotype antibody. However, they showed nocturnal hyperactivity, and greater learning impairment in a patrolling task that is believed to depend upon an intact hippoc us. The data thus demonstrate two important mechanisms: 1. Neutrophil extravasation into the CNS during pneumococcal meningitis influences the pro-inflammatory response and is central to control of the bacterial load, an increase in which may lead to death. 2. Neutrophil-mediated changes in the acute inflammatory response modulate the neuropsychological sequelae in mice that survive pneumococcal meningitis.

Long-term daily access to alcohol alters dopamine-related synthesis and signaling proteins in the rat striatum

Publisher: Elsevier BV

Date: 12-2012

DOI: 10.1016/J.NEUINT.2012.08.013

Abstract: Chronic alcohol exposure can adversely affect neuronal morphology, synaptic architecture and associated neuroplasticity. However, the effects of moderate levels of long-term alcohol intake on the brain are a matter of debate. The current study used 2-DE (two-dimensional gel electrophoresis) proteomics to examine proteomic changes in the striatum of male Wistar rats after 8 months of continuous access to a standard off-the-shelf beer in their home cages. Alcohol intake under group-housed conditions during this time was around 3-4 g/kg/day, a level below that known to induce physical dependence in rats. After 8 months of access rats were euthanased and 2-DE proteomic analysis of the striatum was conducted. A total of 28 striatal proteins were significantly altered in the beer drinking rats relative to controls. Strikingly, many of these were dopamine (DA)-related proteins, including tyrosine hydroxylase (an enzyme of DA biosynthesis), pyridoxal phosphate phosphatase (a co-enzyme in DA biosynthesis), DA and cAMP regulating phosphoprotein (a regulator of DA receptors and transporters), protein phosphatase 1 (a signaling protein) and nitric oxide synthase (which modulates DA uptake). Selected protein expression changes were verified using Western blotting. We conclude that long-term moderate alcohol consumption is associated with substantial alterations in the rat striatal proteome, particularly with regard to dopaminergic signaling pathways. This provides potentially important evidence of major neuroadaptations in dopamine systems with daily alcohol consumption at relatively modest levels.

Asymmetric suppression of components in binary aldehyde mixtures: Behavioral studies in the laboratory rat

Publisher: Oxford University Press (OUP)

Date: 27-10-2007

DOI: 10.1093/CHEMSE/BJL049

Abstract: The aim of the present study was to assess component interaction in the perception of the 2 aldehydes butanal and heptanal when presented in binary mixtures to rats. A further aim was to develop a behavioral paradigm for testing suppression of components in mixtures using rodent subjects. Thirsty rats were initially trained to discriminate between the 2 aldehydes butanal and heptanal in an olfactometer using a go/no-go discrimination task. This involved rats learning to place their noses in a sniff port where odors were presented and to lick a tube for water reward when one of the aldehydes was presented (S+) while withholding licking at the tube to the other, unrewarded, aldehyde (S-). A mixture condition was then introduced into the task, whereby a proportion of trials involved presentation of a combination of the 2 aldehydes as an additional unrewarded condition. Rats readily learned to withhold licking on trials when the mixture was presented. The concentration of the nonrewarded (S-) aldehyde in the mixture was then systematically decreased, whereas the concentration of the S+ component was held constant. This eventually caused the S+ component in the mixture to suppress detection of the S-, as shown by an increasing number of lick responses (false alarms) on trials when the mixture was presented. These suppressing effects occurred well above the detection threshold for the S- aldehyde presented alone. Results showed asymmetric suppression in the mixture condition such that butanal suppressed detection of heptanal at much lower concentrations than vice versa. A second experiment showed that when both butanal and heptanal were present in a binary mixture at the same concentration (10(-6) volume %), then rats responded to the mixture as if only butanal was present. These findings are discussed in terms of butanal having higher mobility and being able to compete more effectively than heptanal for occupation of shared receptor sites.

Sedative and hypothermic effects of γ-hydroxybutyrate (GHB) in rats alone and in combination with other drugs: Assessment using biotelemetry

Publisher: Elsevier BV

Date: 08-2009

DOI: 10.1016/J.DRUGALCDEP.2009.03.004

Abstract: The recreational drug gamma-hydroxybutyrate (GHB) has euphoric effects and can induce sedation and body temperature changes. GHB is frequently combined with other recreational drugs although these interactions are not well characterised. The present study used biotelemetry to provide a fine-grained analysis of the effects of GHB on body temperature and locomotor activity in freely moving rats, and investigated interactions between GHB and 3,4-methylenedioxymeth hetamine (MDMA), meth hetamine (METH) and various antagonist drugs. GHB (1000mg/kg) caused profound sedation for more than 2h and a complex triphasic effect on body temperature: an initial hypothermia (5-40min), followed by hyperthermia (40-140min), followed again by hypothermia (140-360min). A lower GHB dose (500mg/kg) also caused sedation but only a hypothermic effect that lasted up to 6h. The dopamine D(1) receptor antagonist SCH 23390 (1mg/kg), the opioid antagonist naltrexone (1mg/kg), the benzodiazepine antagonist flumazenil (10mg/kg), and the 5-HT(2A/2C) receptor antagonist ritanserin (1mg/kg) did not prevent the overall sedative or body temperature effects of GHB (1000mg/kg). However the GABA(B) antagonist SCH 50911 (50mg/kg) prevented the hyperthermia induced by GHB (1000mg/kg). Repeated daily administration of GHB (1000mg/kg) produced tolerance to the sedative and hyperthermic effects of the drug and cross-tolerance to the sedative effects of the GABA(B) receptor agonist baclofen (10mg/kg). A high ambient temperature of 28 degrees C prevented the hypothermia obtained with GHB (500mg/kg) at 20 degrees C, while GHB (500mg/kg) reduced the hyperthermia and hyperactivity produced by co-administered doses of MDMA (5mg/kg) or METH (1mg/kg) at 28 degrees C. These results further confirm a role for GABA(B) receptors in the hypothermic and sedative effects of GHB and show an interaction between GHB and MDMA, and GHB and METH, that may be relevant to the experience of recreational users who mix these drugs.

In vitro and in vivo pharmacokinetics and metabolism of synthetic cannabinoids CUMYL-PICA and 5F-CUMYL-PICA

Publisher: Springer Science and Business Media LLC

Date: 10-03-2017

DOI: 10.1007/S11419-017-0361-1

Abstract: CUMYL-PICA [1-pentyl- N -(2-phenylpropan-2-yl)-1 H -indole-3-carboxamide] and 5F-CUMYL-PICA [1-(5-fluoropentyl)- N -(2-phenylpropan-2-yl)-1 H -indole-3-carboxamide] are recently identified recreationally used/abused synthetic cannabinoids, but have uncharacterized pharmacokinetic profiles and metabolic processes. This study characterized clearance and metabolism of these compounds by human and rat liver microsomes and hepatocytes, and then compared these parameters with in vivo rat plasma and urine s ling. It also evaluated hypothermia, a characteristic cannabimimetic effect. Incubation of CUMYL-PICA and 5F-CUMYL-PICA with rat and human liver microsomes suggested rapid metabolic clearance, but in vivo metabolism was prolonged, such that parent compounds remained detectable in rat plasma 24 h post-dosing. At 3 mg/kg (intraperitoneally), both compounds produced moderate hypothermic effects. Twenty-eight metabolites were tentatively identified for CUMYL-PICA and, coincidentally, 28 metabolites for 5F-CUMYL-PICA, primarily consisting of phase I oxidative transformations and phase II glucuronidation. The primary metabolic pathways for both compounds resulted in the formation of identical metabolites following terminal hydroxylation or dealkylation of the N -pentyl chain for CUMYL-PICA or of the 5-fluoropentyl chain for 5F-CUMYL-PICA. These data provide evidence that in vivo elimination of CUMYL-PICA, 5F-CUMYL-PICA and other synthetic cannabinoids is delayed compared to in vitro modeling, possibly due to sequestration into adipose tissue. Additionally, the present data underscore the need for careful selection of metabolites as analytical targets to distinguish between closely related synthetic cannabinoids in forensic settings.

Neural activation during cat odor-induced conditioned fear and 'trial 2' fear in rats

Publisher: Elsevier BV

Date: 2005

DOI: 10.1016/J.NEUBIOREV.2005.04.009

Abstract: Exposure to cat odor, an innate threat stimulus for rats, engages a conditioning process whereby the environment in which the odor was experienced comes to elicit fear. Additionally, response to cat odor appears to change with repeated exposure, with benzodiazepines having an anxiolytic effect upon first, but not second, cat odor exposure. We explored the neural correlates of these two phenomena using Fos immunohistochemistry. Rats were exposed to cat odor (a worn cat collar) and were allowed to hide from this stimulus. A 'trial 1' group was perfused after a single exposure, and a 'trial 2' group after two exposures. A 'context' group was exposed to cat odor once, then perfused after re-exposure to the odor-paired context. Trial 1, trial 2 and context groups showed similar defensive responses including avoidance and hiding. The trial 1 group showed Fos expression in limbic, hypothalamic and brainstem regions associated with defensive behavior. The trial 2 group showed a similar pattern although with less activation in the lateral septum, anterior and ventromedial hypothalamus, and dorsolateral periaqueductal gray. The context-exposed group showed Fos expression in a subset of the regions activated by cat odor itself: the dorsal premammillary nucleus, ventrolateral periaqueductal grey, cuneiform nucleus and locus ceruleus. Little activation was seen in the amygdala or hippoc us. These results show that stimuli associated with predatory threat come to activate similar brain regions to the threat stimulus itself.

Body temperature and cardiac changes induced by peripherally administered oxytocin, vasopressin and the non‐peptide oxytocin receptor agonist WAY 267,464: a biotelemetry study in rats

Publisher: Wiley

Date: 15-05-2014

DOI: 10.1111/BPH.12613

Novel molecular changes induced by Nrg1 hypomorphism and Nrg1-cannabinoid interaction in adolescence: A hippocampal proteomic study in mice

Publisher: Frontiers Media SA

Date: 2013

DOI: 10.3389/FNCEL.2013.00015

Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions

Publisher: Wiley

Date: 17-10-2019

DOI: 10.1111/EPI.16355

Sex differences in acute cannabis effects revisited: Results from two randomized, controlled trials

Publisher: Wiley

Date: 22-12-2021

DOI: 10.1111/ADB.13125

Abstract: Some evidence suggests that males and females may differ in their responses to acute cannabis effects, including subjective drug effects and behavioural effects, and cannabinoid pharmacokinetics. This is significant given current changes to cannabis‐related policies and, in consequence, increased cannabis accessibility. The present study combines data from two randomized controlled trials to investigate possible differences among males ( n = 21) and females ( n = 19) in the acute effects of vaporized cannabis containing 13.75 mg Δ9‐tetrahydrocannabinol (THC), with and without cannabidiol (CBD 13.75 mg). To control for differences in the timing of assessments, peak (or peak change from baseline) scores were calculated for a range of measures including subjective drug effects, cognitive performance, cardiovascular effects, and plasma concentrations of THC, CBD, and their respective primary metabolites. While THC elicited robust and significant changes in all but one outcome measure relative to placebo, relatively few sex differences were observed after controlling for BMI and plasma THC concentrations. Relative to females, males performed better overall on a ided attention task (DAT) and had higher peak plasma concentrations of 11‐nor‐9‐carboxy‐THC (11‐COOH‐THC). Males and females did not differ with respect to plasma concentrations of any other analyte, subjective drug effects, or cardiovascular measures. These data indicate an absence of systematic sex differences in acute cannabis effects given a moderate dose of vaporized cannabis. They do not preclude the possibility that sex differences may emerge with higher THC doses or with other commonly used routes of administration (e.g., orally administered oils or edibles).

Biologically meaningful scents: a framework for understanding predator–prey research across disciplines

Publisher: Wiley

Date: 26-04-2017

DOI: 10.1111/BRV.12334

Abstract: Fear of predation is a universal motivator. Because predators hunt using stealth and surprise, there is a widespread ability among prey to assess risk from chemical information - scents - in their environment. Consequently, scents often act as particularly strong modulators of memory and emotions. Recent advances in ecological research and analytical technology are leading to novel ways to use this chemical information to create effective attractants, repellents and anti-anxiolytic compounds for wildlife managers, conservation biologists and health practitioners. However, there is extensive variation in the design, results, and interpretation of studies of olfactory-based risk discrimination. To understand the highly variable literature in this area, we adopt a multi-disciplinary approach and synthesize the latest findings from neurobiology, chemical ecology, and ethology to propose a contemporary framework that accounts for such disparate factors as the time-limited stability of chemicals, highly canalized mechanisms that influence prey responses, and the context within which these scents are detected (e.g. availability of alternative resources, perceived shelter, and ambient physical parameters). This framework helps to account for the wide range of reported responses by prey to predator scents, and explains, paradoxically, how the same in idual predator scent can be interpreted as either safe or dangerous to a prey animal depending on how, when and where the cue was deposited. We provide a hypothetical ex le to illustrate the most common factors that influence how a predator scent (from dingoes, Canis dingo) may both attract and repel the same target organism (kangaroos, Macropus spp.). This framework identifies the catalysts that enable dynamic scents, odours or odorants to be used as attractants as well as deterrents. Because effective scent tools often relate to traumatic memories (fear and/or anxiety) that cause future avoidance, this information may also guide the development of appeasement, enrichment and anti-anxiolytic compounds, and help explain the observed variation in post-traumatic-related behaviours (including post-traumatic stress disorder, PTSD) among erse terrestrial taxa, including humans.

Differential behavioural and neurochemical outcomes from chronic paroxetine treatment in adolescent and adult rats: A model of adverse antidepressant effects in human adolescents?

Publisher: Oxford University Press (OUP)

Date: 18-02-2011

DOI: 10.1017/S146114571100006X

Fasting and exercise increase plasma cannabinoid levels in THC pre-treated rats: an examination of behavioural consequences

Publisher: Springer Science and Business Media LLC

Date: 03-04-2014

DOI: 10.1007/S00213-014-3532-3

Abstract: Δ(9)-Tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, accumulates in fat tissue where it can remain for prolonged periods. Under conditions of increased fat utilisation, blood cannabinoid concentrations can increase. However, it is unclear whether this has behavioural consequences. Here, we examined whether rats pre-treated with multiple or single doses of THC followed by a washout would show elevated plasma cannabinoids and altered behaviour following fasting or exercise manipulations designed to increase fat utilisation. Behavioural impairment was measured as an inhibition of spontaneous locomotor activity or a failure to successfully complete a treadmill exercise session. Fat utilisation was indexed by plasma free fatty acid (FFA) levels with plasma concentrations of THC and its terminal metabolite (-)-11-nor-9-carboxy-∆(9)-tetrahydrocannabinol (THC-COOH) also measured. Rats given daily THC (10 mg/kg) for 5 days followed by a 4-day washout showed elevated plasma THC-COOH when fasted for 24 h relative to non-fasted controls. Fasted rats showed lower locomotor activity than controls suggesting a behavioural effect of fat-released THC. However, rats fasted for 20 h after a single 5-mg/kg THC injection did not show locomotor suppression, despite modestly elevated plasma THC-COOH. Rats pre-treated with THC (5 mg/kg) and exercised 20 h later also showed elevated plasma THC-COOH but did not differ from controls in their likelihood of completing 30 min of treadmill exercise. These results confirm that fasting and exercise can increase plasma cannabinoid levels. Behavioural consequences are more clearly observed with pre-treatment regimes involving repeated rather than single THC dosing.

In vitro and in vivo pharmacological evaluation of the synthetic cannabinoid receptor agonist EG-018

Publisher: Elsevier BV

Date: 06-2020

DOI: 10.1016/J.PBB.2020.172918

A role for oxytocin and 5-HT1A receptors in the prosocial effects of 3,4 methylenedioxymethamphetamine (ecstasy)

Publisher: Elsevier BV

Date: 05-2007

DOI: 10.1016/J.NEUROSCIENCE.2007.02.032

Abstract: The drug 3,4 methylenedioxymeth hetamine (MDMA ecstasy) has a widely documented ability to increase feelings of love and closeness toward others. The present study investigated whether oxytocin, a neuropeptide involved in affiliative behavior, may play a role in this effect. A moderate (5 mg/kg, i.p.) dose of MDMA increased social interaction in male Wistar rats, primarily by increasing the amount of time rats spent lying adjacent to each other. MDMA (5 mg/kg) activated oxytocin-containing neurons in the supraoptic and paraventricular nuclei of the hypothalamus, as shown by Fos immunohistochemistry. MDMA (5 mg/kg i.p.) also increased plasma oxytocin levels and this effect was prevented by pre-treatment with the 5-HT(1A) antagonist N-[2-[4-(2-methyoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate salt (WAY 100,635 1 mg/kg i.p.). The oxytocin receptor antagonist tocinoic acid (20 microg, i.c.v.) had no effect on social behavior when given alone but significantly attenuated the facilitation of social interaction produced by MDMA (5 mg/kg). The 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)-tetraline) (8-OH-DPAT, 0.25 mg/kg, i.p.) increased social behavior in a similar way to MDMA and this effect was also significantly attenuated by tocinoic acid. Taken together, these results suggest that oxytocin release, stimulated by MDMA through 5-HT(1A) receptors, may play a key role in the prosocial effects of MDMA and underlie some of the reinforcing effects of the drug.

Clinical trials of medicinal cannabis for appetite-related symptoms from advanced cancer: A survey of preferences, attitudes and beliefs among patients willing to consider participation

Publisher: Wiley

Date: 11-2016

DOI: 10.1111/IMJ.13224

Abstract: Australian clinical trials are planned to evaluate medicinal cannabis in a range of clinical contexts. To explore the preferences, attitudes and beliefs of patients eligible and willing to consider participation in a clinical trial of medicinal cannabis for poor appetite and appetite-related symptoms from advanced cancer. A cross-sectional anonymous survey was administered from July to December 2015 online and in eight adult outpatient palliative care and/or cancer services. Respondents were eligible if they were ≥18 years, had advanced cancer and poor appetite/taste problems/weight loss and might consider participating in a medicinal cannabis trial. Survey items focused on medicinal rather than recreational cannabis use and did not specify botanical or pharmaceutical products. Items asked about previous medicinal cannabis use and preferences for delivery route and invited comments and concerns. There were 204 survey respondents, of whom 26 (13%) reported prior medicinal cannabis use. Tablets/capsules were the preferred delivery mode (n = 144, 71%), followed by mouth spray (n = 84, 42%) and vaporiser (n = 83, 41%). Explanations for preferences (n = 134) most commonly cited convenience (n = 66 49%). A total of 82% (n = 168) of respondents indicated that they had no trial-related concerns, but a small number volunteered concerns about adverse effects (n = 14) or wanted more information/advice (n = 8). Six respondents volunteered a belief that cannabis might cure cancer, while two wanted assurance of efficacy before participating in a trial. Justification of modes other than tablets/capsules and variable understanding about cannabis and trials will need addressing in trial-related information to optimise recruitment and ensure that consent is properly informed.

The synthesis and pharmacological evaluation of adamantane-derived indoles: Cannabimimetic drugs of abuse

Publisher: American Chemical Society (ACS)

Date: 17-04-2013

DOI: 10.1021/CN400035R

MDMA (ecstacy), methamphetamine and their combination: Long-term changes in social interaction and neurochemistry in the rat

Publisher: Springer Science and Business Media LLC

Date: 17-03-2004

DOI: 10.1007/S00213-004-1786-X

Abstract: 3,4-Methylenedioxymeth hetamine (MDMA) and meth hetamine (METH) are illicit drugs that are increasingly used in combination. The acute and long-term effects of MDMA/METH combinations are largely uncharacterised. The current study investigated the behavioural, thermal and neurotoxic effects of MDMA and METH when given alone or in combined low doses. Male rats received four injections, one every 2 h, of vehicle, MDMA (2.5 or 5 mg/kg per injection), METH (2.5 or 5 mg/kg per injection) or combined MDMA/METH (1.25+1.25 mg/kg per injection or 2+2 mg/kg per injection). Drugs were given at an ambient temperature of 28 degrees C to simulate hot nightclub conditions. Body temperature, locomotor activity and head-weaving were assessed during acute drug administration while social interaction, anxiety-related behavior on the emergence test and neurochemical parameters were assessed 4-7 weeks later. All treatments acutely increased locomotor activity, while pronounced head-weaving was seen with both MDMA/METH treatments and the higher dose METH treatment. Acute hyperthermia was greatest with the higher dose MDMA/METH treatment and was also seen with MDMA but not METH treatment. Several weeks after drug administration, both MDMA/METH groups, both METH groups and the higher dose MDMA group showed decreased social interaction relative to controls, while both MDMA/METH groups and the lower dose MDMA group showed increased anxiety-like behaviour on the emergence test. MDMA treatment caused 5-HT and 5-HIAA depletion in several brain regions, while METH treatment reduced dopamine in the prefrontal cortex. Combined MDMA/METH treatment caused 5-HT and 5-HIAA depletion in several brain regions and a unique depletion of dopamine and DOPAC in the striatum. These results suggest that MDMA and METH in combination may have greater adverse acute effects (head-weaving, body temperature) and long-term effects (decreased social interaction, increased emergence anxiety, dopamine depletion) than equivalent doses of either drug alone.

Perinatal exposure to Δ⁹-tetrahydrocannabinol alters heroin-induced place conditioning and Fos-immunoreactivity

Publisher: Springer Science and Business Media LLC

Date: 25-05-2006

DOI: 10.1038/SJ.NPP.1300770

Abstract: In the present study, the effects of perinatal exposure to Delta(9)-tetrahydrocannabinol (THC) on heroin-induced place conditioning and Fos-immunoreactivity (Fos-IR) were examined. Male albino Wistar rats (N=104) were pretreated with vehicle (n=52) or 5 mg/kg THC (n=52) from postnatal days 4 through 14. At approximately 8 weeks of age, 72 rats were ided into six equal groups (n=12 per group) and injected subcutaneously (s.c.) with vehicle, 0.5, or 2.0 mg/kg heroin and tested in an unbiased two-compartment place conditioning task. In vehicle-pretreated rats, 2.0 mg/kg but not 0.5 mg/kg heroin produced a significant place preference. Perinatal THC exposure significantly enhanced the rewarding properties of both doses of heroin. In the second experiment, 32 rats were ided into four equal groups (n=8 per group) and injected with vehicle or 0.5 mg/kg heroin s.c. and perfused 2-h later. Fos-IR was examined in several brain regions directly or indirectly involved in reward. Acute administration of heroin in vehicle pretreated rats increased Fos-IR in the central, medial, and dorsomedial caudate putamen (CPu), nucleus accumbens (NAC, core and shell regions), lateral septum, islands of Calleja-major (ICjM), bed nucleus of the stria terminalis (BNST), central nucleus of the amygdala (CEA), dorsolateral and dorsomedial periaqueductal gray (PAG), ventral tegmental area (VTA), Edinger-Westphal nucleus (EW). Perinatal THC exposure significantly increased heroin-induced Fos-IR in the dorsomedial CPu. Conversely, perinatal THC exposure reduced heroin-induced Fos-IR in the NAC (shell), BNST, CEA, dorsolateral and lateral PAG, VTA, and EW. The present study demonstrates an increase in the rewarding properties of heroin following exposure to THC at an early age and provides new evidence regarding possible neural correlates underlying this behavioral alteration. Neuropsychopharmacology (2006) 31, 58-69. doi:10.1038/sj.npp.1300770 published online 25 May 2005.

The Effects of Lithium Carbonate Supplemented with Nitrazepam on Sleep Disturbance during Cannabis Abstinence

Publisher: American Academy of Sleep Medicine (AASM)

Date: 15-10-2015

DOI: 10.5664/JCSM.5090

Aggregation in quads but not pairs of rats exposed to cat odor or bright light

Publisher: Elsevier BV

Date: 07-2012

DOI: 10.1016/J.BEPROC.2012.03.014

Abstract: In many prey species aggregation of in iduals is a defensive strategy commonly employed in response to predators and predator-related cues. However, very little work has explored this adaptive response in laboratory rats. It is known that in idual rats show characteristic defensive responses to predator odors, such as hiding, avoidance, inhibition of foraging, feeding and reproduction, and risk assessment directed toward the odor source. However, whether these species-typical responses in in iduals are altered in the presence of other conspecifics is yet to be characterized. The present study therefore examined the defensive response of groups of two rats (dyads) or four rats (quads) to two unconditioned stressors: bright ambient light and cat odor (a 2g ball of cat fur). The dyads and quads were formed from familiar cage mates and test sessions (20 min) occurred in a large open arena (1200 mm(2)) to which the rats had been extensively habituated under dark conditions. The results showed that when quads of rats were exposed to either cat odor or bright light in this arena, they showed characteristic increases in close social proximity, termed "huddling". A tight grouping of 3 (triplet) or 4 (quad) rats was commonly seen in response to cat fur, while triplets were more commonly seen in response to bright light. Interestingly there was no evidence for increased social proximity in dyads exposed to either stressor, only in quads. However, cat odor caused other signs of fear (such as decreased locomotor activity and increased defecation) in both quads and dyads. It is concluded that huddling is a rodent defensive strategy in rats when anxiogenic stimuli are encountered by larger groups of rats.

Erratum to: Composition and Use of Cannabis Extracts for Childhood Epilepsy in the Australian Community (Scientific Reports, (2018), 8, 1, (10154), 10.1038/s41598-018-28127-0)

Publisher: Springer Science and Business Media LLC

Date: 02-08-2018

DOI: 10.1038/S41598-018-30164-8

Abstract: A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Serotonin (1A) receptor involvement in acute 3,4- methylenedioxymethamphetamine (MDMA) facilitation of social interaction in the rat

Publisher: Elsevier BV

Date: 06-2005

DOI: 10.1016/J.PNPBP.2005.04.009

Abstract: The current study assessed whether various co-administered serotonin (5-HT) receptor antagonists could prevent some of the acute behavioral effects of 3,4-methylenedioxymeth hetamine (MDMA, "Ecstasy") in rats. In the social interaction test, MDMA (5 mg/kg) significantly increased the duration of total social interaction between two conspecifics meeting for the first time. Microanalysis showed that MDMA increased adjacent lying and approach behaviours while reducing anogenital sniffing. MDMA (5 mg/kg) also caused elements of the serotonin syndrome including low body posture and piloerection. In the emergence test, MDMA significantly increased hide time and emergence latency indicating increased anxiety-like behavior. Pretreatment with the 5HT 1A receptor antagonist, WAY 100635 (1 mg/kg), prevented MDMA-induced increases in social interaction and markers of the serotonin syndrome while the 5-HT 1B receptor antagonist GR 55562 (1 mg/kg) and 5-HT 2A receptor antagonist ketanserin (1 mg/kg) were ineffective. The 5-HT 2B/2C receptor antagonist, SB 206553 (2 mg/kg), prevented MDMA-induced prosocial effects but caused pronounced thigmotaxis (hyperactivity at the periphery of the testing chamber). The anxiogenic effect of MDMA on the emergence test was not prevented by pretreatment with any of the 5-HT receptor antagonists tested. These results indicate that prosocial effect of MDMA may involve 5-HT 1A and possibly 5-HT 2B/2C receptors. In contrast, MDMA-induced generalised anxiety, as measured by the emergence test, seems unlikely to involve the 5-HT 1A, 5-HT 1B or 5-HT 2A, 5-HT 2B or 5-HT 2C receptors.

Effects of the cannabinoid receptor agonist CP 55,940 and the cannabinoid receptor antagonist SR 141716 on intracranial self-stimulation in Lewis rats

Publisher: Elsevier BV

Date: 11-2001

DOI: 10.1016/S0024-3205(01)01366-2

Abstract: Lewis rats were trained to self-stimulate the medial forebrain bundle (MFB) using a rate-frequency paradigm. They were then tested for the effects of the cannabinoid receptor agonist CP 55,940, the selective cannabinoid receptor antagonist SR 141716 and the dopamine D1 receptor antagonist SCH 23390. CP 55,940 (0, 10, 25 and 50 microg/kg i.p.) had no effect on MFB self-stimulation behaviour as assessed by the M50, the stimulation frequency at which half-maximal response rates were obtained. With SR 141716, only a very high dose (20 mg/kg i.p.) caused a significant inhibition of the rewarding efficacy of the stimulation. This was seen as an increase in the M50. All other doses of SR 141716 (0, 1, 3, 10 mg/kg i.p.) were ineffective in modulating the M50. By comparison, a relatively low dose (0.06 mg/kg i.p.) of SCH 23390 caused a large increase in M50. These results indicate a relatively modest influence, if any at all, of exogenous or endogenous cannabinoids on reward-relevant neurotransmission.

Chronic repetitive transcranial magnetic stimulation is antidepressant but not anxiolytic in rat models of anxiety and depression

Publisher: Elsevier BV

Date: 11-2005

DOI: 10.1016/J.PSYCHRES.2005.07.008

Abstract: Transcranial magnetic stimulation (TMS) has been proposed as a treatment for depression and anxiety disorders. While the antidepressant effect has been modelled in animals, there have been few attempts to examine a possible anxiolytic effect of repetitive TMS (rTMS) in animal models. We administered 18 days of rTMS to male Sprague-Dawley rats. On days 10 through 18, rats were tested in several anxiety models (social interaction, emergence, elevated plus-maze, and predator odor avoidance) and in the forced swim test. No group differences were apparent on any of the anxiety models, while TMS produced an antidepressant effect in the forced swim test. Interestingly, on day 1 of the forced swim test, the home cage control group displayed increased swimming behaviour compared with sham-treated animals, suggesting an observable level of stress may have accompanied sham treatment. The results from the forced swim test suggested that TMS had modest antidepressant properties, but it did not show anxiolytic properties in the models examined. The study also suggested that stress associated with handling should be taken into account in the interpretation of TMS studies in animals.

Fear, risk assessment, and playfulness in the juvenile rat

Publisher: American Psychological Association (APA)

Date: 2006

DOI: 10.1037/0735-7044.120.1.49

Abstract: The effects of predatory odors on play were assessed in juvenile rats. When rats were exposed directly to a collar previously worn by a cat, play was abolished and remained suppressed for up to 6 days. Providing rats with an opportunity to hide did not alter cat odor's ability to reduce their play. Rat play was also suppressed shortly after they were exposed to cat odor in their home cage, and a substantial amount of risk assessment behavior was present up to 24 hr later. Trimethylthiazoline, a component found in fox feces, only reduced play during exposure. These data suggest that predatory odor-induced reductions in play may provide a useful model for gaining insight into the consequences of fear and anxiety in young animals.

Endocannabinoid dysregulation in cognitive and stress-related brain regions in the Nrg1 mouse model of schizophrenia

Publisher: Elsevier BV

Date: 2017

DOI: 10.1016/J.PNPBP.2016.08.006

Abstract: The endocannabinoid system is dysregulated in schizophrenia. Mice with heterozygous deletion of neuregulin 1 (Nrg1 HET mice) provide a well-characterised animal model of schizophrenia, and display enhanced sensitivity to stress and cannabinoids during adolescence. However, no study has yet determined whether these mice have altered brain endocannabinoid concentrations. Nrg1 application to hippoc al slices decreased 2-arachidonoylglycerol (2-AG) signalling and disrupted long-term depression, a form of synaptic plasticity critical to spatial learning. Therefore we specifically aimed to examine whether Nrg1 HET mice exhibit increased 2-AG concentrations and disruption of spatial learning. As chronic stress influences brain endocannabinoids, we also sought to examine whether Nrg1 deficiency moderates adolescent stress-induced alterations in brain endocannabinoids. Adolescent Nrg1 HET and wild-type (WT) mice were submitted to chronic restraint stress and brain endocannabinoid concentrations were analysed. A separate cohort of WT and Nrg1 HET mice was also assessed for spatial learning performance in the Morris Water Maze. Partial genetic deletion of Nrg1 increased anandamide concentrations in the amygdala and decreased 2-AG concentrations in the hypothalamus. Further, Nrg1 HET mice exhibited increased 2-AG concentrations in the hippoc us and impaired spatial learning performance. Chronic adolescent stress increased anandamide concentrations in the amygdala, however, Nrg1 disruption did not influence this stress-induced change. These results demonstrate for the first time in vivo interplay between Nrg1 and endocannabinoids in the brain. Our results demonstrate that aberrant Nrg1 and endocannabinoid signalling may cooperate in the hippoc us to impair cognition, and that Nrg1 deficiency alters endocannabinoid signalling in brain stress circuitry.

Evidence for an interaction between CB1cannabinoid and oxytocin receptors in food and water intake

Publisher: Elsevier BV

Date: 09-2004

DOI: 10.1016/J.NEUROPHARM.2004.06.002

Knowledge and attitudes of Australian general practitioners towards medicinal cannabis: A cross-sectional survey

Publisher: BMJ

Date: 06-2018

DOI: 10.1136/BMJOPEN-2018-022101

Abstract: To examine the knowledge and attitudes of Australian general practitioners (GP) towards medicinal cannabis, including patient demand, GP perceptions of therapeutic effects and potential harms, perceived knowledge and willingness to prescribe. A cross-sectional survey completed by 640 GPs (response rate=37%) attending multiple-topic educational seminars in five major Australian cities between August and November 2017. Number of patients enquiring about medicinal cannabis, perceived knowledge of GPs, conditions where GPs perceived it to be beneficial, willingness to prescribe, preferred models of access, perceived adverse effects and safety relative to other prescription drugs. The majority of GPs (61.5%) reported one or more patient enquiries about medicinal cannabis in the last three months. Most felt that their own knowledge was inadequate and only 28.8% felt comfortable discussing medicinal cannabis with patients. Over half (56.5%) supported availability on prescription, with the preferred access model involving trained GPs prescribing independently of specialists. Support for use of medicinal cannabis was condition-specific, with strong support for use in cancer pain, palliative care and epilepsy, and much lower support for use in depression and anxiety. The majority of GPs are supportive or neutral with regards to medicinal cannabis use. Our results highlight the need for improved training of GPs around medicinal cannabis, and the discrepancy between GP-preferred models of access and the current specialist-led models.

Rats discriminate individual cats by their odor: Possible involvement of the accessory olfactory system

Publisher: Elsevier BV

Date: 09-2008

DOI: 10.1016/J.NEUBIOREV.2008.05.011

Abstract: Social behavior in mammals often relies upon the discrimination of same-species in iduals via olfactory processing of unique chemosensory signatures. The ability to identify in iduals from a different species by their odor (heterospecific discrimination) is less well documented. Here we used a habituation-dishabituation paradigm to demonstrate that rats can discriminate in idual cats by their odor. Rats were repeatedly exposed to a collar previously worn by a domestic cat. Strong initial defensive responses (hiding in a small box and vigilant "head out" behavior from the box entrance) habituated with repeated exposure to the same collar. Brain activation following repeated presentation of the same odor - as indexed by c-Fos expression - also habituated in accessory olfactory regions (mitral and granular layers of the posterior accessory olfactory bulb and posteroventral medial amygdala), as well as regions involved in defensive behavior, including the ventromedial and dorsal premammillary hypothalamic nuclei, basolateral amygdala and periaqueductal grey. When a collar taken from a different cat was presented to habituated rats, defensive responses (hiding, vigilance, suppression of grooming) were dishabituated, and c-Fos expression was reinstated in the accessory olfactory system and in defense-related hypothalamic, amygdaloid and brainstem nuclei. Results indicate that rats may process and store details of the chemosensory signatures of in idual predators using the accessory olfactory system.

Does urbanization lead to parallel demographic shifts across the world in a cosmopolitan plant?

Publisher: Cold Spring Harbor Laboratory

Date: 14-08-2023

DOI: 10.1101/2023.08.14.552623

Abstract: Urbanization is occurring globally, leading to dramatic environmental changes that are altering the ecology and evolution of species. In particular, the expansion of human infrastructure and the loss and fragmentation of natural habitats in cities is predicted to increase genetic drift and reduce gene flow by reducing the size and connectivity of populations. Alternatively, the “urban facilitation model” suggests that some species will have greater gene flow into and within cities leading to higher ersity and lower differentiation in urban populations. These alternative hypotheses have not been contrasted across multiple cities. Here, we used the genomic data from the Global Urban Evolution project (GLUE), to study the effects of urbanization on non-adaptive evolutionary processes of white clover ( Trifolium repens ) at a global scale. We found that white clover populations presented high genetic ersity and no evidence of a reduction in N e linked to urbanization. On the contrary, we found that urban populations were less likely to experience a recent decrease in effective population size than rural ones. In addition, we found little genetic structure among populations both globally and between urban and rural populations, which showed extensive gene flow between habitats. Interestingly, white clover displayed overall higher gene flow within urban areas than within rural habitats. Our study provides one of the largest comprehensive tests of demographic effects of urbanization and our results contrast the common perception that heavily altered and fragmented urban environments will reduce the effective population size and genetic ersity of populations and contribute to their isolation.

Adolescent oxytocin exposure causes persistent reductions in anxiety and alcohol consumption and enhances sociability in rats.

Publisher: Public Library of Science (PLoS)

Date: 16-11-2011

DOI: 10.1371/JOURNAL.PONE.0027237

Increased anxiety in rats after 3,4-methylenedioxymethamphetamine: Association with serotonin depletion

Publisher: Elsevier BV

Date: 06-2002

DOI: 10.1016/S0014-2999(02)01820-4

Abstract: The long-term behavioural and neurotoxic effects of 3,4-methlyenedioxymeth thetamine (MDMA, "Ecstasy") were examined in rats. Rats were given MDMA (5 mg/kg i.p. once per hour for 4 h) or vehicle injections on each of two consecutive days at an ambient temparature of 28 degrees C. MDMA caused acute hyperthermia and locomotor hyperactivity on both days. Four and six weeks after drug administration the rats previously treated with MDMA showed elevated levels of anxiety-like behaviour in the emergence and social interaction tests, respectively. At 9 weeks post-MDMA, the rats displayed an increase in anxiety on the elevated plus-maze test relative to controls. Ten weeks following treatment the rats were killed and their brains dissected and neurotramitter content analysed using High Performance Liquid Chromotography (HPLC). Rats previously given MDMA showed significantly decreased 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the amygdala, hippoc us and striatum relative to controls. This 5-HT depletion may have a causal role in producing increased anxiety-like behaviours in MDMA-treated rats. These results are consistent with human studies suggesting that exposure to high doses of MDMA may predispose to long-term psychological problems such as anxiety and depression.

Pyrazolo[1,4]diazepines as non-peptidic probes of the oxytocin and vasopressin receptors

Publisher: Elsevier BV

Date: 08-2014

DOI: 10.1016/J.TETLET.2014.06.022

Transmembrane domain Nrg1 mutant mice show altered susceptibility to the neurobehavioural actions of repeated THC exposure in adolescence

Publisher: Oxford University Press (OUP)

Date: 02-2013

DOI: 10.1017/S1461145711001854

Abstract: Heavy cannabis abuse increases the risk of developing schizophrenia. Adolescents appear particularly vulnerable to the development of psychosis-like symptoms after cannabis use. To test whether the schizophrenia candidate gene neuregulin 1 (NRG1) modulates the effects of cannabinoids in adolescence, we tested male adolescent heterozygous transmembrane domain Nrg1 mutant (Nrg1 TM HET) mice and wild type-like littermates (WT) for their neurobehavioural response to repeated Δ9-tetrahydrocannabinol (THC, 10 mg/kg i.p. for 21 d starting on post-natal day 31). During treatment and 48 h after treatment withdrawal, we assessed several behavioural parameters relevant to schizophrenia. After behavioural testing we measured autoradiographic CB1, 5-HT2A and NMDA receptor binding. The hyperlocomotor phenotype typical of Nrg1 mutants emerged after drug withdrawal and was more pronounced in vehicle than THC-treated Nrg1 TM HET mice. All mice were equally sensitive to THC-induced suppression of locomotion. However, mutant mice appeared protected against inhibiting effects of repeated THC on investigative social behaviours. Neither THC nor Nrg1 genotype altered prepulse inhibition. Repeated adolescent THC promoted differential effects on CB1 and 5-HT2A receptor binding in the substantia nigra and insular cortex respectively, decreasing binding in WT while increasing it in Nrg1 TM HET mice. THC also selectively affected 5-HT2A receptor binding in several other regions in WT mice, whereas NMDA receptor binding was only affected in mutant mice. Overall, Nrg1 mutation does not appear to increase the induction of psychotomimetic symptoms by repeated adolescent THC exposure but may attenuate some of its actions on social behaviour and schizophrenia-relevant neurotransmitter receptor profiles.

Cognitive, physical, and mental health outcomes between long-term cannabis and tobacco users

Publisher: Elsevier BV

Date: 04-2018

DOI: 10.1016/J.ADDBEH.2017.12.009

Abstract: Cannabis intoxication adversely affects health, yet persistent effects following short-term abstinence in long-term cannabis users are unclear. This matched-subjects, cross-sectional study compared health outcomes of long-term cannabis and long-term tobacco-only users, relative to population norms. Nineteen long-term (mean 32.3years of use, mean age 55.7years), abstinent (mean 15h) cannabis users and 16 long-term tobacco users (mean 37.1years of use, mean age 52.9years), matched for age, educational attainment, and lifetime tobacco consumption, were compared on measures of learning and memory, response inhibition, information-processing, sustained attention, executive control, and mental and physical health. Cannabis users exhibited poorer overall learning and delayed recall and greater interference and forgetting than tobacco users, and exhibited poorer recall than norms. Inhibition and executive control were similar between groups, but cannabis users had slower reaction times during information processing and sustained attention tasks. Cannabis users had superior health satisfaction and psychological, somatic, and general health than tobacco users and had similar mental and physical health to norms whilst tobacco users had greater stress, role limitations from emotional problems, and poorer health satisfaction. Long-term cannabis users may exhibit deficits in some cognitive domains despite short-term abstinence and may therefore benefit from interventions to improve cognitive performance. Tobacco alone may contribute to adverse mental and physical health outcomes, which requires appropriate control in future studies.

P2X7 in Bipolar and Depressive Disorders

Publisher: Springer Berlin Heidelberg

Date: 09-11-2013

DOI: 10.1007/978-3-642-40282-1_31

Heat increases 3,4-methylenedioxymethamphetamine self-administration and social effects in rats

Publisher: Elsevier BV

Date: 12-2003

DOI: 10.1016/J.EJPHAR.2003.09.060

Abstract: 3,4-Methylenedioxymeth hetamine (MDMA, "Ecstasy") is a drug frequently used under hot conditions in nightclubs. In rats tested in the social interaction paradigm, greater prosocial effects of MDMA (5.0 mg/kg) were seen at a hot temperature (30 degrees C) relative to normal laboratory temperature (21 degrees C). In the intravenous drug self-administration paradigm, hot temperature (30 degrees C) increased the number of MDMA infusions (0.1, 0.3 or 1.0 mg/kg/infusion) self-administered by rats. Hot temperatures thus appear to affect both the social and reinforcing effects of MDMA.

Contrasting effects of dopamine antagonists and frequency reduction on Fos expression induced by lateral hypothalamic stimulation

Publisher: Elsevier BV

Date: 05-2002

DOI: 10.1016/S0166-4328(01)00441-7

Abstract: To help further identify the reward-relevant regions activated by electrical stimulation of the lateral hypothalamus, Fos expression was quantified in 23 brain regions in naïve, awake rats following non-contingent stimulation with a frequency that supports self-stimulation (100 Hz), a frequency that supports only minimal responding (50 Hz) and a frequency that does not support self-stimulation (25 Hz). Fos expression was also examined in stimulated and unstimulated rats pretreated with SCH 23390 (a dopamine D1 antagonist) or spiperone (a D2-like antagonist), at doses known to greatly inhibit responding for self-stimulation. Lowering the stimulation frequency from 100 to 50 Hz reduced Fos labelling in all areas, except for a few cells immediately surrounding the electrode tip. No differences were observed between unstimulated rats and those receiving 25 Hz stimulation. This suggests that a critical threshold of stimulation is required before other reward-relevant regions in the midbrain and forebrain are recruited with higher frequency stimulation. Pretreatment with SCH 23390 (0.1 mg/kg) inhibited stimulation-induced Fos expression in some key dopamine terminal areas, such as the nucleus accumbens (core and shell) and medial caudate-putamen, but not in directly driven neurons near the stimulation site. In contrast, spiperone (0.1 mg/kg) did not affect the pattern of stimulation-induced Fos expression, but induced immunolabelling in the dorsolateral caudate-putamen, an area associated with the extrapyramidal side-effects of antipsychotic drugs. These results reveal the utility of Fos immunohistochemistry to show how different treatments that alter the rewarding impact of electrical brain stimulation achieve their effects at the neural level.

Acute and residual effects in adolescent rats resulting from exposure to the novel synthetic cannabinoids AB-PINACA and AB-FUBINACA

Publisher: SAGE Publications

Date: 16-01-2017

DOI: 10.1177/0269881116684336

Abstract: Synthetic cannabinoids (SCs) have rapidly proliferated as recreational drugs, and may present a substantial health risk to vulnerable populations. However, information on possible effects of long-term use is sparse. This study compared acute and residual effects of the popular indazole carboxamide SC compounds AB-PINACA and AB-FUBINACA in adolescent rats with ∆ 9 -tetrahydrocannabinol (THC) and control treatments. Albino Wistar rats were injected (i.p.) with AB-PINACA or AB-FUBINACA every second day (beginning post-natal day (PND) 31), first at a low dose (0.2 mg/kg on 6 days) followed by a higher dose (1 mg/kg on a further 6 days). THC-treated rats received equivalent doses of 6 × 1 mg/kg and 6 × 5 mg/kg. During drug treatment, THC, AB-PINACA, and AB-FUBINACA decreased locomotor activity at high and low doses, increased anxiety-like behaviours and audible vocalisations, and reduced weight gain. Two weeks after dosing was completed, all cannabinoid pre-treated rats exhibited object recognition memory deficits. These were notably more severe in rats pre-treated with AB-FUBINACA. However, social interaction was reduced in the THC pre-treated group only. Six weeks post-dosing, plasma levels of cytokines interleukin (IL)-1α and IL-12 were reduced by AB-FUBINACA pre-treatment, while cerebellar endocannabinoids were reduced by THC and AB-PINACA pre-treatment. The acute effects of AB-PINACA and AB-FUBINACA were broadly similar to those of THC, suggesting that acute SC toxicity in humans may be modulated by dose factors, including inadvertent overdose and product contamination. However, some lasting residual effects of these different cannabinoid receptor agonists were subtly different, hinting at recruitment of different mechanisms of neuroadaptation.

Oxytocin directly administered into the nucleus accumbens core or subthalamic nucleus attenuates methamphetamine-induced conditioned place preference

Publisher: Elsevier BV

Date: 03-2012

DOI: 10.1016/J.BBR.2011.11.038

Abstract: Accumulating evidence indicates that the neuropeptide oxytocin (OXY) may modulate reward-related behavioural responses to meth hetamine (METH) administration. Limited research has examined the effect of OXY on METH-induced conditioned place preference (CPP) and little is known about the neural mechanisms involved. A Fos immunohistochemistry study recently demonstrated that peripheral OXY administration reduced METH-induced Fos expression within the nucleus accumbens (NAc) core and subthalamic nucleus (STh) in rats. The current study aimed to (i) investigate the effect of systemically administered OXY on METH-induced CPP, (ii) determine the effectiveness of a single-trial CPP procedure with METH, in order to (iii) evaluate whether pretreatment with OXY injected directly into the NAc core or the STh attenuates METH-induced CPP. Results showed that male Sprague Dawley rats learned to associate unique compartmental cues with METH (1 mg/kg, i.p.) such that they spent more time in the METH-paired compartment and less time in the saline-paired compartment. Pretreatment with systemic OXY (0.6 mg, i.p.), or OXY (0.6 ng, i.c.) microinjected into the NAc core or the STh prior to METH administration attenuated the formation of a CPP to METH. This provides further evidence that OXY acts within either the NAc core or the STh to reduce the rewarding effects of METH administration.

Evidence for an interaction between CB1 cannabinoid and melanocortin MCR-4 receptors in regulating food intake

Publisher: The Endocrine Society

Date: 07-2004

DOI: 10.1210/EN.2004-0059

Abstract: Melanocortin receptor 4 (MCR4) and CB1 cannabinoid receptors independently modulate food intake. Although an interaction between the cannabinoid and melanocortin systems has been found in recovery from hemorrhagic shock, the interaction between these systems in modulating food intake has not yet been examined. The present study had two primary purposes: 1) to examine whether the cannabinoid and melanocortin systems act independently or synergistically in suppressing food intake and 2) to determine the relative position of the CB1 receptors in the chain of control of food intake in relation to the melanocortin system. Rats were habituated to the test environment and injection procedure and then received intracerebroventicular injections of various combinations of the MCR4 receptor antagonist JKC-363, the CB1 receptor agonist Δ9-tetrahydrocannabinol, the MCR4 receptor agonist α-MSH, or the cannabinoid CB1 receptor antagonist SR 141716. Food intake and locomotor activity were then recorded for 120 min. When administrated alone, SR 141716 and α-MSH dose-dependently attenuated baseline feeding, whereas sub-anorectic doses of SR 141716 and α-MSH synergistically attenuated baseline feeding when combined. Δ9-Tetrahydrocannabinol-induced feeding was not blocked by α-MSH, whereas SR 141716 dose-dependently attenuated JKC-363-induced feeding. Locomotor activity was not significantly affected by any drug treatment, suggesting that the observed effects on feeding were not due to a nonspecific reduction in motivated behavior. These findings revealed a synergistic interaction between the cannabinoid and melanocortin systems in feeding behavior. These results further suggested that CB1 receptors are located downstream from melanocortin receptors and CB1 receptor signaling is necessary to prevent the melanocortin system from altering food intake.

The role of the vasopressin V1A receptor in oxytocin modulation of methamphetamine primed reinstatement

Publisher: Elsevier BV

Date: 05-2018

DOI: 10.1016/J.NEUROPHARM.2017.12.036

Abstract: The neuropeptide oxytocin has shown promise as an effective therapy in pre-clinical models of meth hetamine (METH) addiction. The nucleus accumbens core (NAcc) has been identified as an important site for oxytocin to inhibit METH behaviours, although previous findings suggest that the effects of oxytocin in the NAcc are mediated by receptors other than the oxytocin receptor (OTR). Oxytocin has high affinity for the vasopressin V1A receptor (V1AR) which has been implicated in numerous oxytocin-dependent social behaviours. The aim of this study was to investigate the involvement of the V1AR in mediating the effect of oxytocin treatment to reduce METH-primed reinstatement of METH-seeking behaviour. Male rats were trained to self-administer intravenous infusions of METH by lever press during daily 2-h fixed ratio 1 scheduled sessions for 20 days. Following extinction of lever pressing, rats were tested for the effects of oxytocin alone, oxytocin co-administered with a selective V1AR antagonist, or oxytocin co-administered with a selective OTR antagonist, on METH-primed reinstatement, when administered systemically, or when microinjected into the NAcc. Systemic administration of oxytocin prevented METH-primed reinstatement, an effect which was significantly reduced by systemic pre-treatment with a V1AR but not OTR antagonist. Local administration of oxytocin into the NAcc reduced METH-primed reinstatement, but not when the V1AR was blocked. Our results demonstrate a substantial role for the V1AR in mediating the inhibitory effects of oxytocin on METH-primed reinstatement, and indicate the need for investigations into the differential involvement of V1ARs and OTRs in oxytocin-induced reduction of METH-related behaviours.

The direct actions of cannabidiol and 2-arachidonoyl glycerol at GABA_A receptors

Publisher: Elsevier BV

Date: 05-2017

DOI: 10.1016/J.PHRS.2017.02.022

Abstract: Cannabidiol (CBD) is a major non-intoxicating component of cannabis and possesses anti-epileptic, anxiolytic and anti-hyperalgesic properties. The mechanism of action of CBD in producing such effects remains unclear. Despite evidence that some endogenous and synthetic cannabinoids interact with GABA

MDMA, methamphetamine and their combination: Possible lessons for party drug users from recent preclinical research

Publisher: Wiley

Date: 2007

DOI: 10.1080/09595230601036945

Abstract: The substituted hetamines 3,4-methylenedioxymeth hetamine (MDMA, 'Ecstasy') and meth hetamine (METH, 'ice', 'speed') are increasingly popular drugs amongst party-drug users. Studies with humans have investigated the acute and possible long-term adverse effects of these drugs, yet outcomes of such studies are often ambiguous due to a variety of confounding factors. Studies employing animal models have value in determining the acute and long-term effects of MDMA and METH on brain and behaviour. Self-administration studies show that intravenous METH is a particularly potent reinforcer in rats and other species. In contrast, MDMA appears to have powerful effects in enhancing social behaviour in laboratory animals. Brief exposure to MDMA or METH may produce long-term reductions in dopamine, serotonin and noradrenaline in the brain and alterations in the density of various receptor and transporter proteins. However it is still unclear, particularly in the case of MDMA, whether this reflects a 'neurotoxic' effect of the drug. Lasting alterations in social behaviour, anxiety, depressive symptoms and memory have been demonstrated in laboratory rats given MDMA or METH and this matches long-term changes reported in some human studies. Recent laboratory studies suggest that MDMA/METH combinations may produce greater adverse neurochemical and behavioural effects than either drug alone. This is of some concern given recent evidence that party drug users may be frequently exposed to this combination of drugs.

Neural correlates of MDMA (“Ecstasy”)-induced social interaction in rats

Publisher: Informa UK Limited

Date: 02-2009

DOI: 10.1080/17470910802045042

Abstract: The popular drug 3,4 methylenedioxymeth hetamine (MDMA, "Ecstasy", "the Love Drug") produces feelings of love and closeness in humans and induces analogous prosocial and antiaggressive effects in laboratory animals. Here we examined the specific brain regions that may be involved in these prosocial effects. Male Wistar rats were pretreated with a moderate dose of MDMA (5 mg/kg) or vehicle and then either kept alone in a familiar test chamber for 60 min (groups MDMA-ALONE and VEHICLE-ALONE) or allowed to engage in social interaction in the familiar test chamber with an unfamiliar same-sex conspecific for 60 min (groups MDMA-SOCIAL and VEHICLE-SOCIAL). Rats in the MDMA-SOCIAL group showed much greater overall social interaction than rats in the VEHICLE-SOCIAL group, with microanalysis revealing increased general investigation of other rats but decreased anogenital sniffing. Analysis of neural activation across 39 brain regions using Fos immunohistochemistry showed the following results: (1) VEHICLE-SOCIAL and VEHICLE-ALONE groups did not differ in Fos expression, indicating that a social context per se did not affect Fos expression, (2) MDMA-treated groups showed significantly increased Fos expression relative to VEHICLE treated groups in 30 brain regions, (3) the MDMA-SOCIAL group showed augmented Fos expression relative to the MDMA-ALONE group in six brain regions including the caudate-putamen (medial), medial preoptic area, paraventricular thalamic nucleus, central amygdala, ventromedial hypothalamic nucleus, and the medial amygdala (posterodorsal), and (4) the MDMA-SOCIAL group (but not the MDMA-ALONE group) showed augmented Fos expression relative to the VEHICLE groups in the nucleus accumbens, ventral tegmental area and periaqueductal grey. These results indicate that a moderate dose of MDMA given in a social context causes considerably greater brain activation than the same dose given to solitary rats. This activation involves specific neural circuits that are known to regulate affiliative behavior, perhaps by modulating the incentive value of social stimuli. A possible role for the neuropeptide oxytocin in mediating the prosocial effects of MDMA is discussed.

Cannabidiol (CBD) content in vaporized cannabis does not prevent tetrahydrocannabinol (THC)-induced impairment of driving and cognition

Publisher: Springer Science and Business Media LLC

Date: 05-2019

DOI: 10.1007/S00213-019-05246-8

Randomised controlled trial (RCT) of daily aerobic exercise for inpatient cannabis withdrawal: A study protocol

Publisher: Elsevier BV

Date: 10-2017

DOI: 10.1016/J.MHPA.2017.06.002

Automated scoring of novel object recognition in rats

Publisher: Elsevier BV

Date: 06-2008

DOI: 10.1016/J.JNEUMETH.2008.02.006

Abstract: The object recognition task (ORT) has become increasingly popular as a memory test in neuroscience research. Scoring of ORT performance is still mostly done by hand, which can be liable to subjective scoring. To our knowledge, no suited software is available yet since the direction of the nose of the animal cannot be tracked reliably. We have developed a software paradigm that reliably tracks the nose of the rats and have conducted a series of experiments to evaluate the reliability of this newly developed program. We used Wistar rats, which showed good object memory after 1h interval. Subsequently, we used scopolamine (SCOP) to impair the memory performance of the rats. The object exploration was scored by two observers and the automated system. Both observers and the automated system found an impairing drug effect of scopolamine on ORT performance. When using large objects the correlation between the discrimination index d2 of observers was: 0.60 (SCOP) and 0.79 (SAL). However, the correlation between observers and the automated system was quite low: 0.41 (SCOP) and 0.40 (SAL). Reducing the size of the objects increased the reliability between observers and the automated system substantially (0.82-0.87). We conclude that the use of small objects in combination with our program enables reliable automated scoring in the ORT, thus increasing the objectivity and validity of this task.

Toxic by design? Formation of thermal degradants and cyanide from carboxamide-type synthetic cannabinoids CUMYL-PICA, 5F-CUMYL-PICA, AMB-FUBINACA, MDMB-FUBINACA, NNEI, and MN-18 during exposure to hig

Publisher: Springer Science and Business Media LLC

Date: 28-06-2018

DOI: 10.1007/S11419-018-0430-0

Disruptive effects of the prototypical cannabinoid Δ⁹- tetrahydrocannabinol and the fatty acid amide inhibitor URB-597 on go/no-go auditory discrimination performance and olfactory reversal learning in rats

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 06-2011

DOI: 10.1097/FBP.0B013E328345C82B

The effect of cannabidiol on simulated car driving performance: A randomised, double‐blind, placebo‐controlled, crossover, dose‐ranging clinical trial protocol

Publisher: Wiley

Date: 29-07-2020

DOI: 10.1002/HUP.2749

Long-lasting FosB/ΔFosB immunoreactivity in the rat brain after repeated cat odor exposure

Publisher: Elsevier BV

Date: 09-2009

DOI: 10.1016/J.NEULET.2009.06.069

Abstract: Cat odor elicits defensive responses in rats that are modified by repeated exposure to the odor. We explored the neural correlates of this adaptation using FosB/DeltaFosB immunohistochemistry. Rats were given 3 x60 min exposures to either a worn cat collar (repeated cat odor group) or unworn cat collar (control group). Each exposure was separated by 48h. Rats exposed to cat odor initially showed strong defensive responses (decreased contact, increased retreat, and increased fecal pellets), however these responses had habituated by the final exposure. Rats were perfused 24h or 7 days after the final exposure and the brains were processed for FosB/DeltaFosB protein expression. Up-regulation of FosB/DeltaFosB was observed 24h after repeated cat odor exposure in the nucleus accumbens core, caudate putamen, ventrolateral periaqueductal gray, and four hypothalamic regions: lateral hypothalamus, ventromedial hypothalamus, anterior hypothalamic nucleus, and dorsal premammillary nucleus. FosB/DeltaFosB expression remained elevated 7 days after repeated cat odor exposure in the nucleus accumbens core, caudate putamen and anterior hypothalamic nucleus. These findings provide initial evidence that behavioral changes occurring as a result of repeated predatory stress are associated with long-lasting regionally specific neuroadaptations in the brain.

Topiramate moderately reduces the motivation to consume alcohol and has a marked antidepressant effect in rats

Publisher: Wiley

Date: 17-09-2007

DOI: 10.1111/J.1530-0277.2007.00485.X

Abstract: In recent human studies, the anticonvulsant drug topiramate (TPM) has shown efficacy in treating alcohol craving and mood disorders. However, preclinical evidence supporting such effects is surprisingly sparse. Three experiments were conducted here to assess possible anticraving and antidepressant effects of TPM using animal models. In Experiment 1, rats were given 23 weeks ad libitum access to food, water, and either beer (4.44% ethanol v/v) or "near-beer" (a calorie-matched nonalcoholic beer, 0.44% ethanol) in their home cages. They were then restricted to daily 1 hour operant sessions in which they licked for water and either beer or near-beer under a progressive ratio schedule of reinforcement in a lickometer apparatus. The acute effects of TPM on the motivation to consume beer or near-beer were then assessed. The effects of naloxone were also assessed (as a positive control) after TPM testing. In Experiment 2, rats were given 11 weeks of ad libitum home-cage access to food, water, and beer. They then received repeated daily injections of TPM and effects on beer consumption under ad libitum home cage access conditions were monitored. In Experiment 3, the effects of TPM were assessed in the modified Porsolt forced swim test, emergence test, and elevated plus-maze (EPM) using alcohol naïve rats. Topiramate (10, 20, and 40 mg/kg) significantly reduced the motivation to lick for beer, although the maximal effect was moderate in comparison with naloxone (10 mg/kg). However, naloxone, unlike TPM, also reduced responding for near-beer suggesting an alcohol-specific effect of TPM. In Experiment 2, TPM (40 and 80 mg/kg) tended to transiently reduce alcohol consumption in the home cage under ad libitum access but this effect disappeared with repeated administration of the drug. TPM (10 to 80 mg/kg, given twice over 4 hours before test) produced a robust dose-dependent decrease in immobility and increase in active coping strategies in the forced swim test similar to that seen with desipramine (2 x 20 mg/kg). There were modest anxiolytic effects of TPM on the EPM and emergence tests. With acute administration, TPM is moderately effective and relatively selective in reducing the drive to consume alcohol in Wistar rats. This anti-alcohol effect is modest in comparison with naloxone and appears to dissipate under conditions of chronic treatment and ad libitum alcohol access. A marked antidepressant-like effect in the forced swim test and partial anxiolytic effects in other animal models suggests that TPM may be a beneficial treatment for affective disorders. These preliminary results suggest further research is warranted to resolve the mechanisms involved in TPM modulation of both mood and alcohol consumption.

Weekly γ-Hydroxybutyrate Exposure Sensitizes Locomotor Hyperactivity to Low-Dose 3,4-Methylenedioxymethamphetamine in Rats

Publisher: S. Karger AG

Date: 2009

DOI: 10.1159/000253555

Abstract: Users of the popular party drug 3,4-methylenedioxymeth hetamine (MDMA) sometimes report combining MDMA with γ-hydroxybutyrate (GHB) to enhance the pleasurable effects of both drugs. However, very few studies have examined the influences of this drug combination. The present study investigated the development of locomotor sensitization in laboratory rats given 7 once-weekly exposures to either MDMA, GHB or their combination (MDMA/GHB). The drugs were administered at a high ambient temperature (28°C) to mimic nightclub conditions. MDMA (5 mg/kg), given once weekly, produced a progressively greater locomotor and hyperthermic response over time. In contrast, GHB (500 mg/kg) administered weekly produced consistent low levels of locomotor activity and few changes in body temperature. Rats receiving the mixture of MDMA (5 mg/kg) and GHB (500 mg/kg) showed asymptotic levels of sensitized locomotor activity similar to those seen in rats given MDMA alone, but the development of locomotor sensitization was delayed by coadministered GHB. GHB also delayed the development of MDMA-induced hyperthermia. After a washout period of 5 weeks, rats pre-exposed to MDMA, GHB and MDMA/GHB showed no hyperactivity when tested drug-free in the context in which they had previously received drugs, but displayed a sensitized locomotor response to a low challenge dose of MDMA (2.5 mg/kg). The response to a low dose of meth hetamine (0.5 mg/kg) did not differ among groups. Neurochemical analysis using high-performance liquid chromatography revealed few lasting changes in serotonin, dopamine or their metabolites in the striatum or prefrontal cortex of MDMA- or GHB-pre-exposed rats. These results indicate that GHB modulates the locomotor and hyperthermic response to acute MDMA and that pre-exposure to GHB can sensitize the locomotor response to low doses of MDMA.

Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice

Publisher: Public Library of Science (PLoS)

Date: 03-04-2012

DOI: 10.1371/JOURNAL.PONE.0034129

Mephedrone (4-methylmethcathinone, 'meow'): Acute behavioural effects and distribution of Fos expression in adolescent rats

Publisher: Wiley

Date: 13-10-2012

DOI: 10.1111/J.1369-1600.2011.00384.X

Abstract: Mephedrone (4-methylmethcathinone) is a novel recreational drug that has rapidly increased in popularity in recent years. Users report mephedrone as having the stimulant-like qualities of meth hetamine and cocaine, combined with the prosocial, entactogenic effects of 3,4-methylenedioxymeth hetamine (MDMA). Anecdotal and case study reports indicate that mephedrone may have the potential to engender compulsive patterns of use as well as toxicity in overdose. However, there have been almost no neuropharmacological investigations of the drug up to this point. Here we examined the effects of two different mephedrone doses [15 and 30 mg/kg, intraperitoneal (IP)] relative to the well-known stimulant meth hetamine (2 mg/kg IP) in adolescent rats. Rats were injected, assessed for locomotor activity for 60 minutes and then tested in a 10-minute social preference test (measuring time spent in close proximity to a real rat versus a dummy rat). Their brains were then processed using Fos immunohistochemistry to determine patterns of brain activation. Results showed that mephedrone caused profound locomotor hyperactivity at both dose levels while tending to reduce social preference. Patterns of Fos expression with mephedrone resembled a combination of those observed with meth hetamine and MDMA, with particularly strong Fos expression in the cortex, dorsal and ventral striatum, ventral tegmental area (typical of both MDMA and meth hetamine) and supraoptic nucleus (typical of MDMA). These results demonstrate for the first time the powerful stimulant effects of mephedrone in animal models and its capacity to activate mesolimbic regions. These results also provide some empirical basis to user reports that mephedrone subjectively resembles a MDMA/meth hetamine hybrid.

Rubbings deposited by cats elicit defensive behavior in rats.

Publisher: Elsevier BV

Date: 12-2012

DOI: 10.1016/J.PHYSBEH.2012.03.007

Abstract: Laboratory rats display pronounced defensive behaviors when confronted with a range of cat-derived stimuli, including collars worn by a cat, cloths rubbed on a cat, and cat fur. One possible explanation of this phenomenon (the "kairomone hypothesis") is that rats derive a survival advantage by eavesdropping on signals used by cats to communicate with each other. Cats are known to rub their bodies on objects at strategic environmental locations to signal their identity and mating potential to other cats. The current study assessed the sensitivity of laboratory rats to these body rubbings. In Experiment 1, food deprived Sprague-Dawley rats were trained to consume food pellets in one arm of a Y maze. On test day a d cloth was placed near the food pellets that had been rubbed on a location (wall) where a cat had recently engaged in body rubbing. A control cloth and a collar worn by the cat were also tested. The presence of both the body rubbing residue and the cat collar increased latency to eat and decreased amount of food eaten. The disruption of consummatory behavior in the test environment was still evident 24h later in the absence of odor stimuli. Experiment 2 tested the reaction of naïve Wistar rats to body rubbings using a paradigm in which rats were given the opportunity to hide. Relative to a control condition, rats exposed to a cotton pad wiped on a cat body rubbing location showed increased hiding behavior, decreased exploration and reduced stimulus approach and investigation. These defensive responses persisted for up to 4days following a single stimulus exposure. These results suggest that rats eavesdrop readily on body rubbings cats use for identification purposes, providing further support for a kairomone hypothesis of predator odor avoidance.

A cannabinoid receptor antagonist attenuates conditioned place preference but not behavioural sensitization to morphine

Publisher: Elsevier BV

Date: 11-2004

DOI: 10.1016/J.BRAINRES.2004.08.027

Abstract: The present study compared the effects of the cannabinoid receptor antagonist SR 141716 on morphine-induced locomotor sensitization (Experiment 1) and conditioned place preference (CPP, Experiment 2) in male albino Wistar rats. In Experiment 1, rats received seven consecutive daily treatments with morphine (10 mg/kg, SC) in combination with either SR 141716 (0, 0.1, 0.5 or 3.0 mg/kg, IP), or naloxone (10 mg/kg, IP). Three days later, all rats were challenged with a lower dose of morphine (5 mg/kg, SC). Rats pre-treated with morphine showed significantly elevated locomotor activity during the challenge session compared to vehicle-pre-treated animals indicating behavioural sensitization. Prior naloxone, but not SR 141716, co-administration with morphine, significantly attenuated the locomotor sensitization observed. In Experiment 2A, SR 141716 (0.1 mg/kg, IP), co-administered during conditioning, significantly attenuated the place preference produced by morphine (4 mg/kg, SC) in a standard unbiased two compartment place conditioning task. In Experiment 2B, the timing of drug administration and drug doses used were altered to be similar to Experiment 1, such that a comparison between the sensitization and CPP paradigms could be made. Thus, rats were conditioned with morphine (10 mg/kg, SC) combined with SR 141716 (0, 0.1, 0.5 or 3.0 mg/kg, IP) and tested for place preference under the influence of morphine (5 mg/kg, SC). SR 141716 attenuated morphine place preference at a dose (3.0 mg/kg) that did not itself affect place conditioning. Morphine also induced locomotor sensitization in the drug-paired compartment in Experiment 2B which was not blocked by any dose of SR 141716. We conclude that CB1 receptor antagonism modulates the rewarding value of opioids, but not the behavioural sensitization induced by chronic opioid administration.

Medicinal cannabis in Australia, 2016: The cannabis as medicine survey (CAMS-16)

Publisher: AMPCo

Date: 13-08-2018

DOI: 10.5694/MJA17.01247

Abstract: To explore patterns of cannabis use for medical purposes in Australia immediately prior to the 2016 legislation for frameworks for medical cannabis use. Design, setting: Anonymous online survey with convenience s le, April-October 2016. Participants were recruited through online media and at professional and consumer forums. Adults (at least 18 years of age) who reported using a cannabis product for self-identified medical or therapeutic reasons during the preceding 12 months. Consumer characteristics indications and patterns of medical cannabis use perceived benefits and harms views on appropriate availability of medical cannabis. Most of the 1748 participants were men (68.1%) and employed (56.6%), with a mean age of 37.9 years (SD, 13.4 years) and mean reported period of medical cannabis use of 9.8 years (SD, 12.5 years). The most frequent reasons for medical cannabis use were anxiety (50.7%), back pain (50.0%), depression (49.3%), and sleep problems (43.5%). Respondents had used medical cannabis on a mean of 19.9 of the previous 28 days (SD, 10.0 days), spending a mean $68.60 (SD, $85.00) per week, and 83.4% had inhaled the substance. Participants reported high levels of clinical effectiveness and frequent side effects, including drowsiness, ocular irritation, lethargy and memory impairment 17% met DSM-5 criteria for moderate or severe cannabis use disorder. Many reported harms or concerns related to the illicit status of cannabis. Participants believed that medical cannabis should be integrated into mainstream health care, and that products should be required to meet consistency and safety standards. Illicitly sourced cannabis is used to treat a broad range of medical conditions in Australia. Future models of prescribed medical cannabis take consumer patterns of use and demand into consideration.

ABC transporters P-gp and Bcrp do not limit the brain uptake of the novel antipsychotic and anticonvulsant drug cannabidiol in mice

Publisher: PeerJ

Date: 26-05-2016

DOI: 10.7717/PEERJ.2081

Abstract: Cannabidiol (CBD) is currently being investigated as a novel therapeutic for the treatment of CNS disorders like schizophrenia and epilepsy. ABC transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) mediate pharmacoresistance in these disorders. P-gp and Bcrp are expressed at the blood brain barrier (BBB) and reduce the brain uptake of substrate drugs including various antipsychotics and anticonvulsants. It is therefore important to assess whether CBD is prone to treatment resistance mediated by P-gp and Bcrp. Moreover, it has become common practice in the drug development of CNS agents to screen against ABC transporters to help isolate lead compounds with optimal pharmacokinetic properties. The current study aimed to assess whether P-gp and Bcrp impacts the brain transport of CBD by comparing CBD tissue concentrations in wild-type (WT) mice versus mice devoid of ABC transporter genes. P-gp knockout ( Abcb1a/b −∕− ), Bcrp knockout ( Abcg2 −∕− ), combined P-gp/Bcrp knockout ( Abcb1a/b −∕− Abcg2 −∕− ) and WT mice were injected with CBD, before brain and plasma s les were collected at various time-points. CBD results were compared with the positive control risperidone and 9-hydroxy risperidone, antipsychotic drugs that are established ABC transporter substrates. Brain and plasma concentrations of CBD were not greater in P-gp, Bcrp or P-gp/Bcrp knockout mice than WT mice. In comparison, the brain lasma concentration ratios of risperidone and 9-hydroxy risperidone were profoundly higher in P-gp knockout mice than WT mice. These results suggest that CBD is not a substrate of P-gp or Bcrp and may be free from the complication of reduced brain uptake by these transporters. Such findings provide favorable evidence for the therapeutic development of CBD in the treatment of various CNS disorders.

Effects of Bioisosteric Fluorine in Synthetic Cannabinoid Designer Drugs JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135

Publisher: American Chemical Society (ACS)

Date: 08-05-2015

DOI: 10.1021/ACSCHEMNEURO.5B00107

Abstract: Synthetic cannabinoid (SC) designer drugs featuring bioisosteric fluorine substitution are identified by forensic chemists and toxicologists with increasing frequency. Although terminal fluorination of N-pentyl indole SCs is sometimes known to improve cannabinoid type 1 (CB1) receptor binding affinity, little is known of the effects of fluorination on functional activity of SCs. This study explores the in vitro functional activities of SC designer drugs JWH-018, UR-144, PB-22, and APICA, and their respective terminally fluorinated analogues AM-2201, XLR-11, 5F-PB-22, and STS-135 at human CB1 and CB2 receptors using a FLIPR membrane potential assay. All compounds demonstrated agonist activity at CB1 (EC50 = 2.8-1959 nM) and CB2 (EC50 = 6.5-206 nM) receptors, with the fluorinated analogues generally showing increased CB1 receptor potency (∼2-5 times). Additionally, the cannabimimetic activities and relative potencies of JWH-018, AM-2201, UR-144, XLR-11, PB-22, 5F-PB-22, APICA, and STS-135 in vivo were evaluated in rats using biotelemetry. All SCs dose-dependently induced hypothermia and reduced heart rate at doses of 0.3-10 mg/kg. There was no consistent trend for increased potency of fluorinated SCs over the corresponding des-fluoro SCs in vivo. Based on magnitude and duration of hypothermia, the SCs were ranked for potency (PB-22 > 5F-PB-22 = JWH-018 > AM-2201 > APICA = STS-135 = XLR-11 > UR-144).

Nabiximols as an agonist replacement therapy during cannabis withdrawal

Publisher: American Medical Association (AMA)

Date: 03-2014

DOI: 10.1001/JAMAPSYCHIATRY.2013.3947

Abstract: There are no medications approved for treating cannabis dependence or withdrawal. The cannabis extract nabiximols (Sativex), developed as a multiple sclerosis treatment, offers a potential agonist medication for cannabis withdrawal. To evaluate the safety and efficacy of nabiximols in treating cannabis withdrawal. A 2-site, double-blind randomized clinical inpatient trial with a 28-day follow-up was conducted in New South Wales, Australia. Participants included 51 DSM-IV-TR cannabis-dependent treatment seekers. A 6-day regimen of nabiximols (maximum daily dose, 86.4 mg of Δ9-tetrahydrocannabinol and 80 mg of cannabidiol) or placebo with standardized psychosocial interventions during a 9-day admission. Severity of cannabis withdrawal and cravings (Cannabis Withdrawal Scale), retention in withdrawal treatment, and adverse events. Secondary outcomes include postwithdrawal cannabis use, health outcomes, and psychosocial outcomes. Nabiximols treatment significantly reduced the overall severity of cannabis withdrawal relative to placebo (F8,377.97 = 2.39 P = .01), including effects on withdrawal-related irritability, depression, and cannabis cravings. Nabiximols had a more limited, but still positive, therapeutic benefit on sleep disturbance, anxiety, appetite loss, physical symptoms, and restlessness. Nabiximols patients remained in treatment longer during medication use (unadjusted hazard ratio, 3.66 [95% CI, 1.18-11.37] P = .02), with 2.84 the number needed to treat to achieve successful retention in treatment. Participants could not reliably differentiate between nabiximols and placebo treatment (χ21 = 0.79 P = .67), and those receiving nabiximols did not report greater intoxication (F1,6 = 0.22 P = .97). The number (F1,50 = 0.3 P = .59) and severity (F1,50 = 2.69 P = .10) of adverse events did not differ significantly between groups. Both groups showed reduced cannabis use at follow-up, with no advantage of nabiximols over placebo for self-reported cannabis use (F1,48 = 0.29 P = .75), cannabis-related problems (F1,49 = 2.33 P = .14), or cannabis dependence (F1,50 < 0.01 P = .89). In a treatment-seeking cohort, nabiximols attenuated cannabis withdrawal symptoms and improved patient retention in treatment. However, placebo was as effective as nabiximols in promoting long-term reductions in cannabis use following medication cessation. The data support further evaluation of nabiximols for management of cannabis dependence and withdrawal in treatment-seeking populations. anzctr.org.au Identifier: ACTRN12611000398909.

Heart rate variability predicts alcohol craving in alcohol dependent outpatients: Further evidence for HRV as a psychophysiological marker of self-regulation

Publisher: Elsevier BV

Date: 09-2013

DOI: 10.1016/J.DRUGALCDEP.2013.02.025

Abstract: Past research has highlighted an important role of the autonomic nervous system in alcohol dependence and capacity for self-regulation. While previous studies have examined alcohol dependent inpatients, it remains unclear whether resting-state HRV, a potential psychophysiological marker of ones capacity for self-regulation, is related to craving in patients who currently consume alcohol. Thus, the aim of the present study was to determine whether HRV predicts alcohol craving in dependent in iduals in the community. Resting-state HRV and alcohol craving, as indexed by the obsessive compulsive drinking scale, were assessed in 26 alcohol dependent outpatients. Results supported hypotheses indicating that HRV accounts for an additional 12.1% of the variance in craving after controlling for age, anxiety and levels of alcohol consumption. Here we show for the first time that resting-state HRV predicts craving in alcohol dependent outpatients. Results provide important new evidence for a role of the autonomic nervous system in the maintenance of dependence disorders.

Cannabinoid therapies in the management of sleep disorders: A systematic review of preclinical and clinical studies

Publisher: Elsevier BV

Date: 10-2020

DOI: 10.1016/J.SMRV.2020.101339

Intranasal oxytocin in the treatment of anorexia nervosa: Randomized controlled trial during re-feeding

Publisher: Elsevier BV

Date: 2018

DOI: 10.1016/J.PSYNEUEN.2017.10.014

Abstract: Nutritional rehabilitation in anorexia nervosa (AN) is impeded by fear of food, eating and change leading to treatment resistance. Oxytocin (OT) exerts prosocial effects and modulates trust, fear, anxiety and neuroplasticity. The current placebo-controlled RCT examined the effects of intranasal oxytocin (IN-OT) in AN. The aim was to ascertain whether repeated doses of IN-OT enhance treatment outcomes in AN. AN patients self-administered 36 IU IN-OT or placebo daily for 4-6 weeks during hospital treatment. The outcome measures were change in the Eating Disorders Examination (EDE) scale, weight gain, cognitive rigidity, social anxiety, obsessive and autistic symptoms. The effects of the first and last doses of IN-OT were assessed relative to placebo before and after a high-energy afternoon snack, to determine potential d ening of cortisol and anxiety levels by OT. Weight gain was similar in both groups. The EDE eating concern subscale score was significantly lower after IN-OT treatment as was cognitive rigidity. There were no significant differences in social anxiety or any of the other outcomes at follow-up. After four weeks IN-OT, salivary cortisol levels were significantly lowered in anticipation of an afternoon snack compared to placebo. Morning plasma OT levels did not change after chronic IN-OT or with weight restoration. IN-OT might enhance nutritional rehabilitation in AN by reducing eating concern and cognitive rigidity. Lower salivary cortisol levels in response to IN-OT suggest diminished neuroendocrine stress responsiveness to food and eating. Such effects require replication with inclusion of more sensitive subjective measures.

Antipsychotic induced alteration of growth and proteome of rat neural stem cells

Publisher: Springer Science and Business Media LLC

Date: 18-04-2012

DOI: 10.1007/S11064-012-0768-3

Abstract: Neural stem cells (NSCs) play a crucial role in the development and maturation of the central nervous system and therefore have the potential to target by therapeutic agents for a wide variety of diseases including neurodegenerative and neuropsychiatric illnesses. It has been suggested that antipsychotic drugs have significant effects on NSC activities. However, the molecular mechanisms underlying antipsychotic-induced changes of NSC activities, particularly growth and protein expression, are largely unknown. NSCs were treated with either haloperidol (HD 3 μM), risperidone (RS 3 μM) or vehicle (DMSO) for 96 h. Protein expression profiles were studied through a proteomics approach. RS promoted and HD inhibited the growth of NSCs. Proteomics analysis revealed that 15 protein spots identified as 12 unique proteins in HD-, and 20 protein spots identified as 14 proteins in RS-treated groups, were differentially expressed relative to control. When these identified proteins were compared between the two drug-treated groups, 2 proteins overlapped leaving 10 HD-specific and 12 RS-specific proteins. Further comparison of the overlapped altered proteins of 96 h treatment with the neuroleptics-induced overlapped proteins at 24 h time interval (Kashem et al. [40] in Neurochem Int 55:558-565, 2009) suggested that overlapping altered proteins expression at 24 h was decreased (17 proteins i.e. 53 % of total expressed proteins) with the increase of time (96 h) (2 proteins 8 % of total expressed proteins). This result indicated that at early stage both drugs showed common mode of action but the action was opposite to each other while administration was prolonged. The opposite morphological pattern of cellular growth at 96 h has been associated with dominant expression of oxidative stress and apoptosis cascades in HD, and activation of growth regulating metabolic pathways in RS treated cells. These results may explain RS induced repairing of neural damage caused by a wide variety of neural diseases including schizophrenia.

Defensive behavior

Publisher: Elsevier BV

Date: 2005

DOI: 10.1016/J.NEUBIOREV.2005.05.004

Repeated weekly exposure to MDMA, methamphetamine or their combination: Long-term behavioural and neurochemical effects in rats

Publisher: Elsevier BV

Date: 12-01-2007

DOI: 10.1016/J.DRUGALCDEP.2006.06.004

Abstract: In recent work we have documented lasting adverse neurochemical and behavioural effects in rats given short-term 'binge' dosing with methylenedioxymeth hetamine (MDMA, Ecstasy), meth hetamine (METH) or their combination. Here we investigated whether similar effects persist in rats given 16 weekly injections followed by a 10 week period of abstinence. Female rats received MDMA (8 mg/kg, i.p.), METH (8 mg/kg), or a MDMA/METH combination (4 mg/kg MDMA + 4 mg/kg METH), once a week for 16 weeks, with locomotor activity and body temperature measured on weeks 1, 8 and 16. The MDMA and MDMA/METH groups showed acute drug-induced hyperthermia on week 1 only. MDMA-treated rats demonstrated an acute hyperactivity while METH and MDMA/METH treated rats showed pronounced stereotypy. Seven weeks after drug-treatment concluded, a decrease in social interaction was observed in all chronically drug-treated rats. No group differences were evident on the emergence, object recognition or forced swim tests. Neurochemical analysis revealed modest noradrenaline and serotonin depletion in chronically treated rats that was not evident following a single equivalent administration. These results indicate that although chronic, intermittent exposure to MDMA, METH or their combination, may not lead to significant long-term monoamine depletion, lasting adverse behavioural effects may persist, especially those related to social behaviour.

The effects of predator odors in mammalian prey species: A review of field and laboratory studies

Publisher: Elsevier BV

Date: 2005

DOI: 10.1016/J.NEUBIOREV.2005.05.005

Abstract: Prey species show specific adaptations that allow recognition, avoidance and defense against predators. For many mammalian species this includes sensitivity towards predator-derived odors. The typical sources of such odors include predator skin and fur, urine, feces and anal gland secretions. Avoidance of predator odors has been observed in many mammalian prey species including rats, mice, voles, deer, rabbits, gophers, hedgehogs, possums and sheep. Field and laboratory studies show that predator odors have distinctive behavioral effects which include (1) inhibition of activity, (2) suppression of non-defensive behaviors such as foraging, feeding and grooming, and (3) shifts to habitats or secure locations where such odors are not present. The repellent effect of predator odors in the field may sometimes be of practical use in the protection of crops and natural resources, although not all attempts at this have been successful. The failure of some studies to obtain repellent effects with predator odors may relate to (1) mismatches between the predator odors and prey species employed, (2) strain and in idual differences in sensitivity to predator odors, and (3) the use of predator odors that have low efficacy. In this regard, a small number of recent studies have suggested that skin and fur-derived predator odors may have a more profound lasting effect on prey species than those derived from urine or feces. Predator odors can have powerful effects on the endocrine system including a suppression of testosterone and increased levels of stress hormones such as corticosterone and ACTH. Inhibitory effects of predator odors on reproductive behavior have been demonstrated, and these are particularly prevalent in female rodent species. Pregnant female rodents exposed to predator odors may give birth to smaller litters while exposure to predator odors during early life can hinder normal development. Recent research is starting to uncover the neural circuitry activated by predator odors, leading to hypotheses about how such activation leads to observable effects on reproduction, foraging and feeding.

Oxytocin inhibits ethanol consumption and ethanol-induced dopamine release in the nucleus accumbens.

Publisher: Wiley

Date: 25-01-2016

DOI: 10.1111/ADB.12362

Abstract: Alcohol (EtOH) is one of the most widely abused recreational drugs and is arguably the most harmful. However, current treatment options for alcohol-use disorders generally have limited efficacy and poor uptake in the community. In this context, the neuropeptide oxytocin (OXT) has emerged as a promising potential treatment option for a number of substance-use disorders, including alcoholism. The utility of OXT in reducing consumption of and craving for a wide range of substances may lie in its ability to modulate drug-induced neurochemical effects within the mesolimbic dopamine pathway. However, the impact of OXT on EtOH actions in this pathway has yet to be explored. Here, we reveal that an acute intracerebroventricular (icv) infusion of OXT (1 µg/5 µl) attenuated voluntary EtOH (20 percent) self-administration after chronic intermittent access to EtOH for 59 days (28 drinking sessions) in male Wistar rats. Next, we demonstrated that an acute intraperitoneal (ip) injection of EtOH (1.5 g/kg, 15 percent w/v) increased dopamine release within the nucleus accumbens in both EtOH-naive rats and rats that had received 10 daily ip injections of EtOH. Icv OXT completely blocked the EtOH-induced dopamine release in both EtOH-naive and chronically treated rats. The attenuation of EtOH-induced dopamine release by OXT may help to explain the reduced EtOH self-administration observed following icv OXT infusion.

Active coping toward predatory stress is associated with lower corticosterone and progesterone plasma levels and decreased methylation in the medial amygdala vasopressin system

Publisher: Elsevier BV

Date: 08-2014

DOI: 10.1016/J.YHBEH.2014.08.004

Abstract: An active coping style displayed under stress - which involves proactive investigatory responses toward environmental threats - has been associated with reduced vulnerability to psychiatric illness. However, the neurobiological determinants of coping styles are not well understood. When rats are exposed to a naturalistic stressor (cat fur) in a group, some in iduals in the group show robust active investigation of the stimulus while others show a passive response involving retreat, immobility and close aggregation with conspecifics. Here we explored endocrine and epigenetic correlates of these contrasting coping styles. Male Wistar rats (n=48) were exposed to cat fur in groups of 4 and the passive and active responders were identified and assessed for endocrine and epigenetic differences. Three days after the final cat fur exposure, active responders had substantially lower plasma levels of corticosterone and progesterone than passive responders. Plasma and testicular testosterone levels did not differ between active and passive responders. Active responders had markedly less methylation of the AVP CGCG promoter region located at base 4970 in the posterodorsal region of the medial amygdala but did not differ in the methylation status of the CCGG sequence located at base 2243. This is in agreement with prior research suggesting that AVP and progesterone act in opposition within the medial amygdala to modulate stress-related behaviors. The present study reports striking endocrine and epigenetic differences between active and passive responders, providing insight into potential systems involved in the manifestation of differing coping styles.

Defensive Aggregation (Huddling) in Rattus Norvegicus toward Predator Odor: Individual Differences, Social Buffering Effects and Neural Correlates

Publisher: Public Library of Science (PLoS)

Date: 29-07-2013

DOI: 10.1371/JOURNAL.PONE.0068483

Regional c-Fos and FosB/ΔFosB expression associated with chronic methamphetamine self-administration and methamphetamine-seeking behavior in rats

Publisher: Elsevier BV

Date: 03-2012

DOI: 10.1016/J.NEUROSCIENCE.2012.01.004

Abstract: The regional expression of the transcription factors c-Fos and FosB/ΔFosB was examined in rats given acute exposure to intravenous meth hetamine (METH) or repeated intravenous METH self-administration. One group of rats self-administered METH via lever pressing in 2 h sessions every day for 3 weeks and on a final test day received self-administered METH as usual. A second group with the same METH self-administration history received saline infusions on the test day, to induce drug-seeking behavior. Other rats were trained with infusions of intravenous saline that were yoked to the passive delivery of METH in the other two groups. On test day, half of these yoked rats received passive METH infusions for the first time, whereas the others received saline as usual. The results showed that acute METH produced a characteristic signature of Fos expression with elevations in striatal, cortical, and extended amygdala regions. Importantly, rats with a 3-week history of METH self-administration displayed similar regional Fos expression to rats receiving METH for the first time. Rats seeking, but not receiving, METH on the test day had augmented Fos in the lateral hypothalamus, septum, and vertical limb of the diagonal band of Broca, suggesting a primary role for these regions in METH-seeking behavior. Both acute and chronic METH activated orexin-positive cells in the perifornical area of the hypothalamus. FosB/ΔFosB was elevated in the lateral hypothalamus, posterior ventral tegmental area, central amygdala, and dorsal raphe of all the rats with a history of METH self-administration. This occurred regardless of whether they received METH on test day, suggesting presence of the long-lived FosB isoform, ΔFosB. Overall, these results show persistent upregulated regional brain Fos and FosB/ΔFosB expression with chronic METH self-administration and indicate a role for the lateral hypothalamus and lateral septum in METH-seeking behavior.

Regional c-Fos expression induced by peripheral oxytocin administration is prevented by the vasopressin 1A receptor antagonist SR49059

Publisher: Elsevier BV

Date: 10-2016

DOI: 10.1016/J.BRAINRESBULL.2016.10.005

Abstract: Peripherally administered oxytocin induces a wide range of behavioural and physiological effects that are thought to be mediated by the oxytocin receptor (OTR). However, oxytocin also has considerable affinity for the vasopressin 1A receptor (V

Controllability of prestimulation of the medial prefrontal cortex determines the facilitation of self-stimulation and kindled seizures

Publisher: Elsevier BV

Date: 08-1989

DOI: 10.1016/0031-9384(89)90262-X

Abstract: Electrical stimulation of the medial prefrontal cortex (MPC) was administered according to the triadic design typically used to demonstrate learned helplessness. Three groups received either controllable, uncontrollable or no stimulation during the pretreatment phase. The effects of this pretreatment on the acquisition of self-stimulation at the same electrode site were investigated in the second phase of the experiment. Relative to unstimulated controls, both controllable and uncontrollable prestimulation facilitated the acquisition of self-stimulation and produced higher self-stimulation rates. In addition, compared with controllable stimulation, pretreatment with uncontrollable stimulation produced a greater facilitation in self-stimulation rate. The unambiguous demonstration of a behavioural facilitation produced by pretreatment with uncontrollable stimulation is, effectively, the inverse of the typical learned helplessness finding. It was also found, in the second phase of the experiment, that 6 of the 7 rats previously exposed to uncontrollable stimulation developed full class 5 seizures. No behavioural evidence of kindling was seen in any of the other rats or during the prestimulation procedure. These data are interpreted in terms of kindling and stress effects both proximal and distal to the site of stimulation.

Contrasting regional Fos expression in adolescent and young adult rats following acute administration of the antidepressant paroxetine

Publisher: Elsevier BV

Date: 03-2016

DOI: 10.1016/J.BRAINRESBULL.2016.02.008

Abstract: Adolescents and adults may respond differently to antidepressants, with poorer efficacy and greater probability of adverse effects in adolescents. The mechanisms underlying this differential response are largely unknown, but likely relate to an interaction between the neural effects of antidepressants and brain development. We used Fos immunohistochemistry to examine regional differences in adolescent (postnatal day (PND) 28) and young adult (PND 56) male, Wistar rats given a single injection of the selective serotonin reuptake inhibitor paroxetine (10mg/kg). Paroxetine induced widespread Fos expression in both adolescent and young adult rats. Commonly affected areas include the bed nucleus of the stria terminalis (dorsolateral), medial preoptic area, paraventricular hypothalamic and thalamic nuclei and central nucleus of the amygdala. Fos expression was generally lower in adolescents with significantly greater Fos expression observed in young adults in the prelimbic cortex, supraoptic nucleus, basolateral amygdala, lateral parabrachial and Kölliker-Fuse nuclei. However, a small subset of regions showed greater adolescent Fos expression including the nucleus accumbens shell, lateral habenula and dorsal raphe. Paroxetine increased plasma corticosterone concentrations in young adults, but not adolescents. Plasma paroxetine levels were not significantly different between the age groups. These results indicate a different c-Fos signature of acute paroxetine in adolescent rats, with greater activation in key mesolimbic and serotonergic regions, but a more subdued cortical, brainstem and hypothalamic response. This suggests that the atypical response of adolescents to paroxetine may be related to a blunted neuroendocrine response, combined with insufficient top-down regulation of limbic regions involved in reward and impulsivity.

Co-administration of THC and MDMA ('Ecstasy') synergistically disrupts memory in rats

Publisher: Springer Science and Business Media LLC

Date: 16-02-2005

DOI: 10.1038/SJ.NPP.1300692

Abstract: 3,4-Methylenedioxymeth hetamine (MDMA, 'Ecstasy') and cannabis are two of the most commonly used illicit drugs in the western world, and are often used in combination. Very little research has examined their effect on cognitive function or behavior when combined, The present study used a double Y-maze task to examine the acute effect of MDMA and delta9-tetrahydrocannabinol (THC, the principal psychoactive ingredient of cannabis) on mnemonic function in rats, at a range of doses representative of common human use. Experiment I (low doses) examined the effect of 0.25 mg/kg THC and 1.25 mg/kg MDMA alone and together. At these doses MDMA or THC given alone had no effect on working memory, but the co-administered drugs significantly disrupted working memory. Experiment 2 (medium doses) examined the effect of 0.5 mg/kg THC and 2.5 mg/kg MDMA given alone or together. At these doses THC, but not MDMA, impaired working memory. Although MDMA alone had no effect, it exacerbated the impairment due to THC when the drugs were co-administered. Experiment 3 (high doses) examined the effects of 1 mg/kg THC and 5 mg/kg MDMA alone and together. Both drugs significantly impaired memory when given alone, although the impairment due to MDMA was less than that caused by THC. When co-administered at these doses, the drugs caused a major disruption of behavior and this precluded ascribing a mnemonic cause to poor performance on the double Y-maze task Taken together, these experiments demonstrate a synergistic disruption of working memory by acute co-administration of THC and MDMA.

Pilot and Definitive Randomised Double-Blind Placebo-Controlled Trials Evaluating an Oral Cannabinoid-Rich THC/CBD Cannabis Extract for Secondary Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV)

Publisher: Elsevier BV

Date: 10-2017

DOI: 10.1093/ANNONC/MDY300.119

Consumption of high carbohydrate, high fat, and normal chow is equally suppressed by a cannabinoid receptor antagonist in non-deprived rats

Publisher: Elsevier BV

Date: 16-01-2004

DOI: 10.1016/J.NEULET.2003.10.035

Abstract: Administration of the CB1 receptor antagonist SR 141716 [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] suppresses intake of highly palatable (high carbohydrate) food. However, the effects of SR 141716 on intake of foods with varying macronutrient compositions, and in non-deprived animals have not been well studied. In the present study, non-deprived rats were injected intraperitoneally with SR 141716 (0.03-3.0 mg/kg) and presented with a high carbohydrate, high fat, or normal chow diet. Food intake and locomotor activity were recorded for 120 min. Results showed that SR 141716 significantly suppressed food intake irrespective of the composition of the test food without affecting locomotor activity. These data suggest that food deprivation or high palatability of the ingesta are not necessary to observe the suppressive effects of SR 141716 on food intake.

Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial.

Publisher: Elsevier BV

Date: 11-2020

DOI: 10.1016/J.ANNONC.2020.07.020

Modulation of anxiety-related behaviours following lesions of the prelimbic or infralimbic cortex in the rat

Publisher: Elsevier BV

Date: 10-1997

DOI: 10.1016/S0006-8993(97)00810-X

Abstract: A series of experiments examined behavioural and autonomic aspects of stress and anxiety in rats subjected to either: (1) electrolytic lesions of the infralimbic cortex subregion of the medial prefrontal cortex (2) electrolytic lesions of the prelimbic cortex subregion of the medial prefrontal cortex (3) sham lesions of infralimbic or prelimbic cortex (sham control) or (4) no lesions (control). In exploration-based models of anxiety, infralimbic- or prelimbic-lesioned rats spent less time in the centre of an open field and less time on the exposed arms of an elevated plus maze, indicating increased anxiety. Locomotor activity was normal in the lesioned rats when tested in a non-stressful enclosed environment. In a step-down passive avoidance task, infralimbic-lesioned rats stepped down more quickly than controls onto a grid floor where they had been shocked 24 h previously. Prelimbic-lesioned rats were no different to controls on this test, although they showed greater latencies to step down onto the grid floor during conditioning. In a final experiment, indirect calorimetry was used to show that both infralimbic- and prelimbic-lesioned rats have essentially normal alterations in oxygen consumption and energy substrate utilisation when exposed to brief footshock. Thus, the impaired passive avoidance in infralimbic-lesioned rats cannot be attributed to decreased nociception. It is concluded that both the prelimbic and infralimbic regions play a role in anxiety, and that this role may be subtly differentiated. In particular, the infralimbic cortex may have a specific role in mediating the inhibition of behaviours associated with aversive outcomes.

Repeated cannabinoid exposure during perinatal, adolescent or early adult ages produces similar long-lasting deficits in object recognition and reduced social interaction in rats

Publisher: SAGE Publications

Date: 09-01-2006

DOI: 10.1177/0269881106065188

Abstract: There is mounting evidence that chronic cannabis use might result in lasting neurobehavioural changes, although it remains unclear whether vulnerability diminishes with age. The current study compared the effects of cannabinoid exposure at three developmental periods on subsequent measures of memory and anxiety. Male rats aged 4 days (perinatal), 30 days (adolescent) and 56 days (young adult) were injected with vehicle or incremental doses of the cannabinoid receptor agonist CP 55940, daily for 21 consecutive days (0.15, 0.20 or 0.30mg/kg for 7 days per dose, respectively). Following a 28-day drug-free period, working memory was assessed in an object recognition task. One week later, social anxiety was assessed in a social interaction test. Two days later, generalized anxiety was assessed in an emergence test. Results revealed that CP 55940 impaired working memory and social interaction similarly at all three ages. CP 55940 had no effects in five of six emergence test measures, but a modest but significant reduction in anxiety was noted in one measure following adolescent exposure. We conclude that chronic cannabinoid exposure leads to long-term memory impairments and increased anxiety, irrespective of the age at which drug exposure occurrs.

Benzodiazepines Impair the Acquisition and Reversal of Olfactory Go/No-Go Discriminations in Rats

Publisher: American Psychological Association (APA)

Date: 2007

DOI: 10.1037/0735-7044.121.3.527

Abstract: The present study assessed whether benzodiazepines impair the acquisition, performance, and reversal of olfactory and auditory go/no-go discriminations in rats. Experiment 1 showed that midazolam (0.5-2 mg/kg sc) did not affect the performance of a well-learned two-odor olfactory discrimination and moderately facilitated performance of a go/no-go auditory discrimination. Experiment 2 found that midazolam (1 mg/kg) increased the number of errors made in the acquisition of a novel go/no-go olfactory discrimination task and in the reversal of a previously well-learned olfactory discrimination. However, midazolam did not affect the acquisition and reversal of an equivalent auditory discrimination task. Experiment 3 showed that diazepam (1 mg/kg) also impaired the acquisition and reversal of a novel olfactory discrimination task. Taken together, these results indicate that benzodiazepines cause a selective impairment of olfactory discrimination learning. This may reflect an effect of benzodiazepines in the glomerular circuitry of the olfactory bulb and at downstream olfactory processing sites such as the piriform cortex and orbitofrontal cortex.

Inhaled vasopressin increases sociability and reduces body temperature and heart rate in rats

Publisher: Elsevier BV

Date: 08-2014

DOI: 10.1016/J.PSYNEUEN.2014.04.013

Abstract: The neuropeptides vasopressin (AVP) and oxytocin (OT) have therapeutic potential across a range of psychiatric disorders. However, there is uncertainty about the effectiveness of the intranasal route of administration that is often used to deliver these neuropeptides. Recent preclinical studies, typically involving anesthetized or restrained animals, have assessed intranasal AVP or OT effects, and have obtained somewhat inconsistent results. Here we obtained intranasal administration of AVP in rats by nebulizing the peptide (1ml of 5 or 10mg/ml solution) into a small enclosed chamber over a 2min period in which well-habituated, unanesthetized, unrestrained, rats were placed. Rats were immediately removed from the chamber and tested in the social interaction test, or assessed for changes in heart rate and body temperature using biotelemetry. Results showed that rats exposed to nebulized AVP (5 or 10mg/ml) showed increased social proximity (adjacent lying) and decreased anogenital sniffing in the social interaction test. Biotelemetry showed substantial and long lasting (>1h) hypothermic and bradycardic effects of nebulized AVP. These behavioral and physiological effects of nebulized AVP mimic those observed in recent studies with peripherally injected AVP. Plasma AVP concentrations were substantially increased 10min after nebulized AVP, producing levels above those seen with a behaviorally effective injected dose of AVP (0.005mg/kg intraperitoneal). This study thus provides a novel and effective method for neuropeptide administration to rodents.

Mephedrone in Adolescent Rats: Residual Memory Impairment and Acute but Not Lasting 5-HT Depletion

Publisher: Public Library of Science (PLoS)

Date: 18-09-2012

DOI: 10.1371/JOURNAL.PONE.0045473

Regional differences in naloxone modulation of Δ9-THC induced Fos expression in rat brain

Publisher: Elsevier BV

Date: 02-2003

DOI: 10.1016/S0028-3908(02)00364-7

Abstract: Recent behavioral and pharmacological research shows extensive interplay between cannabinoid and opioid neurochemical systems. Here we examined the neuroanatomical basis of this interaction using c-fos immunohistochemistry. We compared Fos immunoreactivity in groups of male albino Wistar rats treated with vehicle, Delta(9)-tetrahydrocannabinol (THC, 10 mg/kg, i.p.), naloxone (10 mg/kg, i.p.) or THC and naloxone in combination. Locomotor activity was depressed in both THC treatment groups and moderately inhibited in rats given naloxone alone. Results showed that naloxone inhibited THC-induced Fos immunoreactivity in several key brain regions including the ventral tegmental area, ventromedial and dorsomedial hypothalamus, central caudate-putamen and ventrolateral periaqueductal grey. Conversely, naloxone and THC had an additive effect on Fos immunoreactivity in the central nucleus of the amygdala, the bed nucleus of the stria terminalis (lateral ision), the insular cortex, and the paraventricular nucleus of the thalamus. These findings complement earlier pharmacological results showing potent modulation of cannabinoid-induced analgesia, appetite and reward by opioids. The inhibitory effects of naloxone on THC-induced ventral tegmentum, hypothalamic and periaqueductal grey Fos expression point to these structures as key sites involved in cannabinoid-opioid interactions.

Cannabis use and non-cancer chronic pain

Publisher: Elsevier BV

Date: 10-2018

DOI: 10.1016/S2468-2667(18)30180-4

Differential protein expression in the corpus callosum (body) of human alcoholic brain

Publisher: Wiley

Date: 25-06-2009

DOI: 10.1111/J.1471-4159.2009.06141.X

Abstract: Neuroimage analysis in alcoholic corpus callosum (CC) suggests that microstructural abnormalities are higher in the genu followed by the body and the splenium. Molecular mechanisms underlying these dysmorphologys are still unclear. Protein expression was performed using the CC body s les [(nine controls, seven uncomplicated, and six complicated (with liver cirrhosis) alcoholics] through proteomics approach. Thirty-nine protein spots in uncomplicated and 60 in complicated alcoholics were differentially altered compared with the control (p < 0.05). Comparison between alcoholic groups revealed that 40% more protein showed altered expression in complicated compared with uncomplicated. This result suggests that alcohol-related liver dysfunction has synergetic effects on brain protein expression. Subregional expression profiles indicate that the highest numbers of region-specific proteins were in the genus followed by the CC body and the splenium. Interestingly, abnormal thiamine cascade was strongly suggested in the genu, and to a lesser extent in the CC body, but no such cascade was observed in the splenium. Therefore, alcohol-induced microstructural damage detected by image analysis in the CC, possibly involves multiple biochemical mechanisms.

Absence of Entourage: Terpenoids Commonly Found inCannabis sativaDo Not Modulate the Functional Activity of Δ⁹-THC at Human CB₁and CB₂Receptors

Publisher: Mary Ann Liebert Inc

Date: 09-2019

DOI: 10.1089/CAN.2019.0016

CUMYL-4CN-BINACA Is an Efficacious and Potent Pro-Convulsant Synthetic Cannabinoid Receptor Agonist

Publisher: Frontiers Media SA

Date: 29-05-2019

DOI: 10.3389/FPHAR.2019.00595

Chronic fluoxetine treatment partly attenuates the long-term anxiety and depressive symptoms induced by MDMA ('Ecstasy') in rats

Publisher: Springer Science and Business Media LLC

Date: 12-11-2004

DOI: 10.1038/SJ.NPP.1300347

Acute Prosocial Effects of Oxytocin and Vasopressin When Given Alone or in Combination with 3,4-Methylenedioxymethamphetamine in Rats: Involvement of the V1A Receptor

Publisher: Springer Science and Business Media LLC

Date: 16-05-2013

DOI: 10.1038/NPP.2013.125

Global urban environmental change drives adaptation in white clover.

Publisher: American Association for the Advancement of Science (AAAS)

Date: 18-03-2022

DOI: 10.1126/SCIENCE.ABK0989

Abstract: Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by s ling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.

Nabiximols for the Treatment of Cannabis Dependence: A Randomized Clinical Trial

Publisher: American Medical Association (AMA)

Date: 09-2019

DOI: 10.1001/JAMAINTERNMED.2019.1993

A brief history of oxytocin and its role in modulating psychostimulant effects.

Publisher: SAGE Publications

Date: 23-01-2013

DOI: 10.1177/0269881112473788

Abstract: Over the past century, the polypeptide oxytocin has played an important role in medicine with major highlights including the identification of its involvement in parturition and the milk let-down reflex. Oxytocin is now implicated in an extensive range of psychological phenomena including reward and memory processes and has been investigated as a treatment for several psychiatric disorders including addiction, anxiety, autism, and schizophrenia. In this review, we first provide an historical overview of oxytocin and describe key aspects of its physiological activity. We then outline some pharmacological limitations in this field of research before highlighting the role of oxytocin in a wide range of behavioral and neuronal processes. Finally, we review evidence for a modulatory role of oxytocin with regard to psychostimulant effects. Key findings suggest that oxytocin attenuates a broad number of cocaine and meth hetamine induced behaviors and associated neuronal activity in rodents. Evidence also outlines a role for oxytocin in the prosocial effects of 3,4-methylenedioxymeth hetamine (MDMA, Ecstasy) in both rodents and humans. Clinical trials should now investigate the effectiveness of oxytocin as a novel intervention for psychostimulant addiction and should aim to determine its specific role in the therapeutic properties of MDMA that are currently being investigated.

Defensive responses of Wistar and Sprague-Dawley rats to cat odour and TMT

Publisher: Elsevier BV

Date: 09-2006

DOI: 10.1016/J.BBR.2006.04.011

Abstract: Cat odour and trimethylthiazoline (TMT) are two predator odours commonly used to study defensive behaviour in rats. However their reported efficacy varies markedly across laboratories. We assessed whether rat strain differences might explain such variation. Wistar and Sprague-Dawley rats were tested for unconditioned and conditioned responses to both odours. Cat odour produced robust unconditioned and conditioned defensive behaviour, with notably stronger effects in Wistar rats. TMT produced limited unconditioned avoidance, but failed to elicit conditioned responses in either strain. Results support suggestions that faeces-derived odours such as TMT are less predictive of a predator threat than those derived from fur or skin, and identify the possibility that strain differences affect the defensive response seen to predator odours.

Constrasting effects of dopaminergic blockade on MDMA and d-amphetamine conditioned taste aversions

Publisher: Elsevier BV

Date: 02-1994

DOI: 10.1016/0091-3057(94)90025-6

David J. Allsop (7.12.1974-2013.8.2018)

Publisher: Wiley

Date: 11-2018

DOI: 10.1111/DAR.12865

High ambient temperature increases intravenous methamphetamine self-administration on fixed and progressive ratio schedules in rats

Publisher: SAGE Publications

Date: 22-08-2008

DOI: 10.1177/0269881107082286

Abstract: Meth hetamine is a drug that is often consumed at dance parties or nightclubs where the ambient temperature is high. The present study determined whether such high ambient temperatures alter intravenous meth hetamine self-administration in the rat. Male Hooded Wistar rats were trained to self-administer intravenous meth hetamine (0.1 mg/kg/infusion) under a fixed ratio 1 (FR1) or progressive ratio (PR) schedule of reinforcement at an ambient temperature of 23 ± 1°C. They were then given their daily self-administration session at a raised ambient temperature of 30 ± 1°C. Meth hetamine self-administration was increased at 30°C under both FR1 and PR reinforcement schedules, with the latter effect indicating that heat enhances the motivation to obtain meth hetamine. High temperatures did not alter self-administration of the D1 receptor agonist SKF 82958 in meth hetamine-experienced rats suggesting some specificity in the meth hetamine effect. When rats were given access to drink isotonic saline solution during meth hetamine self-administration sessions they drank much more solution at 30°C than 23°C. However, availability of isotonic saline to drink did not alter the heat-induced facilitation of meth hetamine self-administration (PR schedule) indicating that the heat effect does not simply reflect increased motivation for intravenous fluids. Hyperthermia was evident in rats self-administering meth hetamine at high ambient temperatures and fluid consumption did not prevent this effect. Heat did not affect blood levels of meth hetamine, or its principal metabolite hetamine indicating that the facilitatory effect of heat did not reflect altered meth hetamine pharmacokinetics. Overall, these results show that high ambient temperatures increase the reinforcing efficacy of meth hetamine and encourage higher levels of drug intake.

Longitudinal trends in the dispensing of psychotropic medications in Australia from 2009-2012: Focus on children, adolescents and prescriber specialty

Publisher: SAGE Publications

Date: 13-06-2014

DOI: 10.1177/0004867414538675

Abstract: Longitudinal trends in the dispensing of antidepressant, antipsychotic and ADHD medications from 2009–2012 were examined according to age and gender of patient and prescriber speciality. Of particular interest were changing trends in the prescription of psychotropic medications to children, adolescents and young adults. Dispensing data for government-subsidised antidepressant, antipsychotic and ADHD medications were obtained from the database maintained by the Department of Human Services. Results were expressed in terms of number of prescriptions dispensed. Over the four- year study period, the dispensing of antidepressants, antipsychotics and ADHD medications showed overall increases of 16.1%, 22.7% and 26.1% respectively. The most rapid percentage increases in antidepressant and antipsychotic dispensing occurred in children aged 10–14 (35.5% and 49.1% respectively), while ADHD medication dispensing rose most rapidly in those aged 20–24 (70.9%). Dispensing to males was more common during childhood for all investigated classes while two-thirds of adult antidepressant prescribing was to female patients. The most commonly prescribed antidepressants varied by age and were as follows: fluoxetine (3–19 year olds), desvenlafaxine (20–24 years) and venlafaxine ( years). Risperidone was the most common antipsychotic dispensed to children under 15, quetiapine to adolescents and young adults (15–24 years), and olanzapine to adults. Methylphenidate was the most common ADHD medication in those aged under 25, and dex hetamine the most common in adults. Most antidepressants and antipsychotics were prescribed by GPs (89.9% and 70.6% respectively), while the majority of ADHD medications were prescribed by paediatricians (59.1%). Dispensing of psychotropic medications increased markedly from 2009 to 2012, with notable age-specific trends. General adherence to treatment guidelines is apparent, yet concerns exist regarding rapid increases in serotonin noradrenaline reuptake inhibitor (SNRI) antidepressant prescribing, the likely overmedication of persons with mild psychological distress, and the increasing use of powerful psychotropic medications in younger populations despite uncertain risk–benefit profiles.

Rats on the grog: Novel pharmacotherapies for alcohol craving

Publisher: Elsevier BV

Date: 09-2004

DOI: 10.1016/J.ADDBEH.2004.06.011

High ambient temperature increases 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-induced Fos expression in a region-specific manner

Publisher: Elsevier BV

Date: 03-2007

DOI: 10.1016/J.NEUROSCIENCE.2006.12.023

Abstract: 3,4-Methylenedioxymeth hetamine (MDMA, "Ecstasy") is a popular drug that is often taken under hot conditions at dance clubs. High ambient temperature increases MDMA-induced hyperthermia and recent studies suggest that high temperatures may also enhance the rewarding and prosocial effects of MDMA in rats. The present study investigated whether ambient temperature influences MDMA-induced expression of Fos, a marker of neural activation. Male Wistar rats received either MDMA (10 mg/kg i.p.) or saline, and were placed in test chambers for 2 h at either 19 or 30 degrees C. MDMA caused significant hyperthermia at 30 degrees C and a modest hypothermia at 19 degrees C. The 30 degrees C ambient temperature had little effect on Fos expression in vehicle-treated rats. However MDMA-induced Fos expression was augmented in 15 of 30 brain regions at the high temperature. These regions included (1) sites associated with thermoregulation such as the median preoptic nucleus, dorsomedial hypothalamus and raphe pallidus, (2) the supraoptic nucleus, a region important for osmoregulation and a key mediator of oxytocin and vasopressin release, (3) the medial and central nuclei of the amygdala, important in the regulation of social and emotional behaviors, and (4) the shell of the nucleus accumbens and (anterior) ventral tegmental area, regions associated with the reinforcing effects of MDMA. MDMA-induced Fos expression was unaffected by ambient temperature at many other sites, and was diminished at high temperature at one site (the islands of Calleja), suggesting that the effect of temperature on MDMA-induced Fos expression was not a general pharmacokinetic effect. Overall, these results indicate that high temperatures accentuate key neural effects of MDMA and this may help explain the widespread use of the drug under hot conditions at dance parties as well as the more hazardous nature of MDMA taken under such conditions.

Oral cannabinoid-rich THC/CBD cannabis extract for secondary prevention of chemotherapy-induced nausea and vomiting: a study protocol for a pilot and definitive randomised double-blind placebo-control

Publisher: BMJ

Date: 09-2018

DOI: 10.1136/BMJOPEN-2017-020745

Abstract: Chemotherapy-induced nausea and vomiting (CINV) remains an important issue for patients receiving chemotherapy despite guideline-consistent antiemetic therapy. Trials using delta-9-tetrahydrocannabinol-rich (THC) products demonstrate limited antiemetic effect, significant adverse events and flawed study design. Trials using cannabidiol-rich (CBD) products demonstrate improved efficacy and psychological adverse event profile. No definitive trials have been conducted to support the use of cannabinoids for this indication, nor has the potential economic impact of incorporating such regimens into the Australian healthcare system been established. CannabisCINV aims to assess the efficacy, safety and cost-effectiveness of adding TN-TC11M, an oral THC/CBD extract to guideline-consistent antiemetics in the secondary prevention of CINV. The current multicentre, 1:1 randomised cross-over, placebo-controlled pilot study will recruit 80 adult patients with any malignancy, experiencing CINV during moderate to highly emetogenic chemotherapy despite guideline-consistent antiemetics. Patients receive oral TN-TC11M (THC 2.5mg/CBD 2.5 mg) capsules or placebo capsules three times a day on day −1 to day 5 of cycle A of chemotherapy, followed by the alternative drug regimen during cycle B of chemotherapy and the preferred drug regimen during cycle C. The primary endpoint is the proportion of subjects attaining a complete response to CINV. Secondary and tertiary endpoints include regimen tolerability, impact on quality of life and health system resource use. The primary assessment tool is patient diaries, which are filled from day −1 to day 5. A subsequent randomised placebo-controlled parallel phase III trial will recruit a further 250 patients. The protocol was approved by ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences. Tilray. 2.0, 9 June 2017. ANZCTR12616001036404 Pre-results.

Moderate alcohol intake is related to increased heart rate variability in young adults: Implications for health and well-being

Publisher: Wiley

Date: 14-08-2013

DOI: 10.1111/PSYP.12134

Abstract: Epidemiological literature indicates that the relationship between alcohol consumption and health outcomes reflects a J-shaped curve such that moderate alcohol consumption confers a protective effect in comparison to abstinence, while heavy consumption is associated with poorer health. While heart rate variability (HRV) may underpin the relationship between drinking and poor health in heavy drinkers, it is unclear whether HRV is increased in moderate, habitual drinkers relative to nonhabitual drinkers. HRV and drinking habits were assessed in 47 volunteers. Results supported hypotheses suggesting that moderate, habitual drinking increases HRV. Although not supported by a significant interaction between drinking group and sex, planned follow-up analysis also revealed that these findings may be specific to males. Regardless, results highlight HRV as a candidate mechanism for the findings reported in the epidemiological literature.

A validated method for the simultaneous quantification of cannabidiol, Δ⁹‐tetrahydrocannabinol, and their metabolites in human plasma and application to plasma samples from an oral cannabid

Publisher: Wiley

Date: 12-2020

DOI: 10.1002/DTA.2947

Abstract: Cannabidiol (CBD) and Δ 9 ‐tetrahydrocannabinol (THC) are the two best known and most extensively studied phytocannabinoids within Cannabis sativa . An increasing number of preclinical studies and clinical trials have been conducted with one or both compounds, often probing their therapeutic effects in conditions such as paediatric epilepsy, anxiety disorders or chronic pain. Accurate monitoring of THC and CBD and their metabolites is essential for tracking treatment adherence and pharmacokinetics. However, fully validated methods for the comprehensive analysis of major Phase I CBD metabolites are yet to be developed due to a historical lack of commercially available reference material. In the present study, we developed, optimised and validated a method for the simultaneous quantification of CBD, THC and their major Phase I metabolites 6‐hydroxy‐CBD (6‐OH‐CBD), 7‐hydroxy‐CBD (7‐OH‐CBD), 7‐carboxy‐CBD (7‐COOH‐CBD), 11‐hydroxy‐tetrahydrocannabinol (11‐OH‐THC) and 11‐carboxy‐tetrahydrocannabinol (11‐COOH‐THC) as per Food and Drug Administration (FDA) guidelines for bioanalytical method validation. The method is accurate, reproducible, sensitive and can be carried out in high‐throughput 96‐well formats, ideal for larger scale clinical trials. Deuterated internal standards for each analyte were crucial to account for variable matrix effects between plasma lots. The application of the method to plasma s les, taken from people who had been administered oral CBD as part of an open‐label trial of CBD effects in anxiety disorders, demonstrated its immediate utility in ongoing and upcoming clinical trials. The method will prove useful for future studies involving CBD and/or THC and can likely accommodate the inclusion of additional metabolites as analytical reference materials become commercially available.

Changes in cigarette and alcohol use during cannabis abstinence

Publisher: Elsevier BV

Date: 05-2014

DOI: 10.1016/J.DRUGALCDEP.2014.01.022

Abstract: Cannabis causes lower mortality and morbidity than alcohol and tobacco so it is clinically important if quitting cannabis is associated with substitution with these substances. This study tests if cannabis is substituted with alcohol and/or tobacco during cannabis abstinence, and factors predicting such substitution. A secondary analysis of a prospective community based study quantified cannabis, alcohol and tobacco use with Timeline Follow-back during a two-week voluntary cannabis abstinence and at one-month follow-up in non-treatment seeking cannabis users (n=45). Cannabis use was verified by urine THC-COOH levels. Alcohol use increased by 8 standard units (SU d=0.48)/week and cigarette use by 14 cigarettes/week (d=0.29) during cannabis abstinence. Those using less of each substance at baseline had greater increases during cannabis abstinence (alcohol P<0.0001, tobacco P=0.01). There was a decrease in alcohol (-4.8 SU, d=-0.29) and tobacco (-13 cigarettes/week, d=-0.26) use at follow-up, when most participants (87%, n=39) had resumed cannabis use. Increased cigarette use was predicted by cannabis withdrawal related sleep difficulty (insomnia) (P=0.05), restlessness (P=0.03) and physical symptoms (P=0.02). Neither alcohol nor cigarette use increased significantly in those (13.3%, n=6) who remained abstinent from cannabis through to follow-up. Abstaining from cannabis was associated with increases in alcohol and tobacco use that decreased with resumption of cannabis use however there were no increases in in iduals who remained abstinent from cannabis at one-month follow-up. Tobacco use did not increase in those experiencing milder cannabis withdrawal symptoms. Research on substitution in treatment seekers during outpatient cannabis abstinence is needed.

International conference on memory (ICOM-4), University of New South Wales, Sydney, Australia, 16-21 July 2006 ecstasy/MDMA and memory symposium

Publisher: SAGE Publications

Date: 11-2007

DOI: 10.1177/0269881107077377

Stress-induced changes in respiratory quotient, energy expenditure and locomotor activity in rats: effects of midazolam

Publisher: Springer Science and Business Media LLC

Date: 12-1994

DOI: 10.1007/BF02247481

Deletion of TDO2, IDO-1 and IDO-2 differentially affects mouse behavior and cognitive function

Publisher: Elsevier BV

Date: 10-2016

DOI: 10.1016/J.BBR.2016.06.018

Abstract: Tryptophan, an amino acid involved in routine energy metabolism, is a key modulator of sickness behaviors associated with inflammatory states and also plays roles in some psychiatric disorders. Tissue concentrations of tryptophan are regulated primarily by the enzymes indoleamine 2,3-dioxygenase 1 (IDO1), IDO2 and tryptophan 2,3-dioxygenase (TDO, encoded by TDO2). Altered IDO1 and TDO activities have been linked to the perturbed serotonergic neurotransmission that may underlie certain psychopathologies. Here we assessed mice genetically modified to be deficient in IDO1, IDO2 or TDO2 for their behavior and cognitive function using an automated home cage system, the IntelliCage™. A well-established behavioural and cognitive test battery was applied during two periods (Runs 1 and 2, "R1" and "R2") separated by one month. Various tryptophan-related neurochemicals also were measured in brain extracts. IDO1(-/-) mice displayed remarkable reductions of early diurnal exploration in the IntelliCage and this persisted in R2. In contrast, early diurnal hyperactivity was observed in IDO2(-/-) mice in both R1 and R2. TDO2(-/-) mice displayed increased diurnal and nocturnal exploration, but only in R2. Cognitive assessment suggested enhanced reference memory in IDO2(-/-) mice in a complex patrolling task, while TDO deficiency was associated with enhanced performance in complex patrolling and discrimination reversal tasks. Neurochemical measures showed attenuated brain serotonin levels in IDO1(-/-) mice and augmented tryptophan and serotonin levels in TDO2(-/-) animals, respectively. No neurochemical alterations were detected in IDO2(-/-) mice. Taken together, these findings reveal complex and dissimilar patterns of behavioral and cognitive changes induced by knockout of three different tryptophan-metabolizing enzymes.

Oxytocin and addiction: Recent preclinical advances and future clinical potential

Publisher: Cambridge University Press

Date: 11-04-2011

DOI: 10.1017/CBO9781139017855.018

Pharmacokinetics of Phytocannabinoid Acids and Anticonvulsant Effect of Cannabidiolic Acid in a Mouse Model of Dravet Syndrome

Publisher: American Chemical Society (ACS)

Date: 05-11-2019

DOI: 10.1021/ACS.JNATPROD.9B00600

Kinetic and metabolic profiles of synthetic cannabinoids NNEI and MN‐18

Publisher: Wiley

Date: 28-09-2017

DOI: 10.1002/DTA.2262

The cardiovascular and behavioral response to cat odor in rats: Unconditioned and conditioned effects

Publisher: Elsevier BV

Date: 04-2001

DOI: 10.1016/S0006-8993(01)02227-2

Abstract: Cardiovascular and behavioral responses were recorded in rats during exposure to cat odor. Rats were habituated to an open rectangular arena that contained a small enclosed wooden box in which they could hide. On day 1 of the experiment, after 30 min in the apparatus, rats were presented with a piece of fabric collar for 60 min. On day 2, rats were presented with an identical piece of fabric collar, except that it had been worn by a cat and therefore exuded cat odor. On day 3, rats were again presented with an unworn cat collar, to determine any conditioned responses to the environment or stimulus (collar) previously associated with cat odor. Results showed significantly increased blood pressure and decreased activity during exposure to cat odor as well as avoidance of the odor stimulus and an increase in vigilance and risk-assessment measures. No significant change in heart rate was found during cat odor exposure. On day 3, a transient increase in blood pressure was seen as well as reduced activity and a range of defensive behaviors. This suggests some conditioning of fear to a context in which cat odor had previously been experienced. Heart rate was also significantly decreased on day 3. A transient rise in blood pressure was also seen when the unworn cat collar was placed into the apparatus on day 3, suggesting a conditioned response to a stimulus that has been previously associated with cat odor. This study demonstrates that a natural stressful stimulus can induce both unconditioned and conditioned autonomic and behavioral responses.

Changes in respiratory quotient elicited in rats by a conditioned stimulus predicting food

Publisher: Elsevier BV

Date: 1998

DOI: 10.1016/S0031-9384(97)00429-0

Abstract: The present study examined whether changes in energy expenditure and energy substrate utilization occur in rats exposed to a conditioned stimulus that signals food. In a differential conditioning procedure, rats were given conditioning sessions where one of two cues (either a flashing light or buzzer) predicted a carbohydrate-rich meal (CS+) while the other cue predicted no food (CS-). In two subsequent test sessions, indirect calorimetry was used to measure respiratory quotient, energy expenditure, and locomotor activity before, during, and after a 15-min CS+ or CS- presentation. The CS+ was found to significantly increase respiratory quotient, indicating a shift in the energy substrate being utilized toward carbohydrate. The CS+ also increased energy expenditure and locomotor activity, but these effects were more variable across rats. It is concluded that respiratory quotient may rise in anticipation of a carbohydrate-rich meal. Possible mechanisms underlying this effect are discussed.

Adolescent exposure to oxytocin, but not the selective oxytocin receptor agonist TGOT, increases social behavior and plasma oxytocin in adulthood

Publisher: Elsevier BV

Date: 05-2014

DOI: 10.1016/J.YHBEH.2014.03.002

Abstract: There are indications that exposing adolescent rodents to oxytocin (OT) may have positive "trait-changing" effects resulting in increased sociability and decreased anxiety that last well beyond acute drug exposure and into adulthood. Such findings may have relevance to the utility of OT in producing sustained beneficial effects in human psychiatric conditions. The present study further examined these effects using an intermittent regime of OT exposure in adolescence, and using Long Evans rats, that are generally more sensitive to the acute prosocial effects of OT. As OT has substantial affinity for the vasopressin V1a receptor (V1aR) in addition to the oxytocin receptor (OTR), we examined whether a more selective peptidergic OTR agonist - [Thr4, Gly7]-oxytocin (TGOT) - would have similar lasting effects on behavior. Male Long Evans rats received OT or TGOT (0.5-1mg/kg, intraperitoneal), once every three days, for a total of 10 doses during adolescence (postnatal day (PND) 28-55). Social and anxiety-related behaviors were assessed during acute administration as well as later in adulthood (from PND 70 onwards). OT produced greater acute behavioral effects than TGOT, including an inhibition of social play and reduced rearing, most likely reflecting primary sedative effects. In adulthood, OT but not TGOT pretreated rats displayed lasting increases in social interaction, accompanied by an enduring increase in plasma OT. These findings confirm lasting behavioral and neuroendocrine effects of adolescent OT exposure. However, the absence of such effects with TGOT suggests possible involvement of the V1aR as well as the OTR in this ex le of developmental neuroplasticity.

A Double-Blind Randomized Controlled Trial of Oxytocin Nasal Spray in Prader Willi Syndrome

Publisher: Wiley

Date: 30-06-2014

DOI: 10.1002/AJMG.A.36653

Abstract: In iduals with Prader-Willi syndrome (PWS) have a significant reduction in the number of oxytocin-producing neurons (42%) in the hypothalamic paraventricular nucleus. A number of animal studies and observations of humans show that lesions in this region can produce PWS-like symptoms. Given the evidence for potential oxytocin deficiency, we tested the effects of a course of intranasal oxytocin on PWS symptoms. Thirty in iduals with PWS aged 12-30 years participated in an 18-week randomized double-blind placebo-controlled crossover trial. Participants received 8 weeks of oxytocin and 8 weeks of placebo with a minimum 2-week washout period. The first 11 participants received the following oxytocin doses: 24 IU (twice daily) B.I.D for participants 16 years and over and 18 IU B.I.D for participants 13-15 years. The dose was increased for the remaining 18 participants to 40 IU B.I.D for participants 16 years and over and 32 IU B.I.D for 13-15 years. Measures used to assess changes were standardized well-accepted measures, including the Developmental Behavior Checklist-Monitor, Parent, Teacher, and Adult The Yale-Brown Obsessive Compulsive Scale The Dykens Hyperphagia questionnaire Reading The Mind in the Eyes Test Epworth Sleepiness Scale and the Movie Stills. Oxytocin had little impact on any measure. The only significant difference found between the baseline, oxytocin, and placebo measures was an increase in temper outbursts (P = 0.023) with higher dose oxytocin. The lack of effect of oxytocin nasal spray may reflect the importance of endogenous release of oxytocin in response to exogenous oxytocin.

Exercise increases plasma THC concentrations in regular cannabis users

Publisher: Elsevier BV

Date: 12-2013

DOI: 10.1016/J.DRUGALCDEP.2013.07.031

Abstract: The major psychoactive ingredient of cannabis, Δ(9)-tetrahydrocannabinol (THC) accumulates in fat tissue from where it slowly diffuses back into blood. THC pre-treated rats can show elevated plasma cannabinoid levels when subjected to conditions that promote fat utilization, such as fasting. Here we examine whether fasting and exercise increase plasma THC concentrations in regular cannabis users. Fourteen regular cannabis users completed 35 min of exercise on a stationary bicycle in either a fed or overnight fasted state. Plasma cannabinoid levels were assessed prior to exercise, immediately post-exercise and 2h post-exercise. Plasma s les were also analyzed for indices of lipolysis (free fatty acids (FFA) and glycerol). Exercise induced a small, statistically significant increase in plasma THC levels accompanied by increased plasma FFA and glycerol levels. Exercise-induced increases in plasma THC concentrations were positively correlated with body mass index. Fasting induced a significant increase in plasma FFA levels, and a lowering of blood glucose, but did not significantly alter plasma cannabinoid levels. Here we demonstrate that exercise enhances plasma THC levels in regular cannabis users. The lack of a fasting effect may reflect the modest duration of fasting used which was associated with only a modest increase in fat utilization relative to exercise. Overall, these results suggest that exercise may elevate blood THC levels by releasing dormant THC from fat stores. These data suggest the interpretation of blood THC levels in roadside and workplace tests might be complicated by recent exercise.

Predatory threat induces huddling in adolescent rats and residual changes in early adulthood suggestive of increased resilience.

Publisher: Elsevier BV

Date: 12-2011

DOI: 10.1016/J.BBR.2011.07.058

Abstract: Adolescence is a critical developmental period during which chronic stress and binge alcohol consumption are often seen as environmental risk factors that confer vulnerability to later mental health problems. The current study modelled this using a 2×2 design where male Wistar rats were exposed to intermittent predatory stress (Stress condition: groups of 4 rats given 30 min of cat fur exposure in a large arena, once every 48 h) or intermittent alcohol (Alcohol condition: access to beer for 24 h every 2nd day), or both manipulations given on alternate days (Stress/Alcohol), or no manipulation (Control). The manipulations occurred over a 24 day adolescent window (postnatal day (PND) 33-57) giving a total of 12 cat fur exposures and/or 12 alternate days of beer access. Residual anxiety- and depressive-like behaviours were assessed in early adulthood (PND 58-77). Cat fur exposure was found to elicit a distinct defensive response in which groups of adolescent rats huddled together in the corner of the arena, either in "quads" (all 4 rats bunched together) or "triplets" (3 rats together and one outlier rat). Few approaches to the cat fur occurred and locomotor activity was suppressed relative to Control rats placed in the arena without fur. Huddling continued over the 12 repeated exposures to cat fur, and was temporarily exaggerated when fur from a novel cat was introduced. Interestingly, huddling and conditioned fear in the fur-associated context were most pronounced in rats receiving intermittent alcohol, suggesting that alternate day exposure to alcohol had anxiogenic effects, possibly linked to a hangover state on these days. Predatory stress did not affect overall alcohol consumption relative to rats given alcohol alone, but significantly inhibited weight gain through adolescence and into adulthood. In early adulthood, rats exposed to stress in adolescence, regardless of alcohol exposure, showed significantly reduced immobility in the forced swim test and signs of increased sociability with a novel conspecific in a social interaction paradigm. Overall, these findings suggest greater resilience in adulthood after chronic adolescent stress, indicating that coping with predators may be in some ways a form of early environmental enrichment.

Rapid quantitation of fluoxetine and norfluoxetine in serum by micro-disc solid-phase extraction with high-performance liquid chromatography-ultraviolet absorbance detection

Publisher: Elsevier BV

Date: 05-2004

DOI: 10.1016/J.JCHROMB.2004.01.034

Interactions between cannabidiol and Δ⁹-tetrahydrocannabinol in modulating seizure susceptibility and survival in a mouse model of Dravet syndrome

Publisher: Wiley

Date: 27-07-2020

DOI: 10.1111/BPH.15181

Dark Classics in Chemical Neuroscience: Δ⁹-Tetrahydrocannabinol

Publisher: American Chemical Society (ACS)

Date: 28-01-2019

DOI: 10.1021/ACSCHEMNEURO.8B00651

Abstract: Cannabis ( Cannabis sativa) is the most widely used illicit drug in the world, with an estimated 192 million users globally. The main psychoactive component of cannabis is (-)- trans-Δ

Are blood and oral fluid Δ9-tetrahydrocannabinol (THC) and metabolite concentrations related to impairment? A meta-regression analysis

Publisher: Elsevier BV

Date: 03-2022

DOI: 10.1016/J.NEUBIOREV.2021.11.004

High levels of intravenous mephedrone (4-methylmethcathinone) self-administration in rats: Neural consequences and comparison with methamphetamine

Publisher: SAGE Publications

Date: 05-06-2013

DOI: 10.1177/0269881113490325

Abstract: Mephedrone (MMC) is a relatively new recreational drug that has rapidly increased in popularity in recent years. This study explored the characteristics of intravenous MMC self-administration in the rat, with meth hetamine (METH) used as a comparator drug. Male Sprague-Dawley rats were trained to nose poke for intravenous MMC or METH in daily 2 h sessions over a 10 d acquisition period. Dose-response functions were then established under fixed- and progressive-ratio (FR and PR) schedules over three subsequent weeks of testing. Brains were analyzed ex vivo for striatal serotonin (5-HT) and dopamine (DA) levels and metabolites, while autoradiography assessed changes in the regional density of 5-HT and serotonin transporter (SERT) and DA transporter (DAT) and induction of the inflammation marker translocator protein (TSPO). Results showed that MMC was readily and vigorously self-administered via the intravenous route. Under a FR1 schedule, peak responding for MMC was obtained at 0.1 mg/kg/infusion, versus 0.01 mg/kg/infusion for METH. Break points under a PR schedule peaked at 1 mg/kg/infusion MMC versus 0.3 mg/kg/infusion for METH. Final intakes of MMC were 31.3 mg/kg/d compared to 4 mg/kg/d for METH. Rats self-administering MMC, but not METH, gained weight at a slower rate than control rats. METH, but not MMC, self-administration elevated TSPO receptor density in the nucleus accumbens and hippoc us, while MMC, but not METH, self-administration decreased striatal 5-hydroxyindolacetic acid (5-HIAA) concentrations. In summary, MMC supported high levels of self-administration, matching or exceeding those previously reported with other drugs of abuse.

A nose for death: integrating trophic and informational networks for conservation and management

Publisher: Frontiers Media SA

Date: 26-10-2016

DOI: 10.3389/FEVO.2016.00124

Chronic cannabinoid exposure produces lasting memory impairment and increased anxiety in adolescent but not adult rats

Publisher: SAGE Publications

Date: 12-2004

DOI: 10.1177/0269881104047277

Abstract: Although many studies have examined the acute behavioural effects of cannabinoids in rodents, few have examined the lasting effects of cannabinoids at different developmental ages. This study compared lasting effects of cannabinoid exposure occurring in adolescence to that occurring in early adulthood. Forty, 30-day old (adolescent) and 18, 56-day old (adult) female albino Wistar rats were injected with vehicle or incremental doses of the cannabinoid receptor agonist (-)- cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]- trans-4-(3-hydroxypropyl) cyclohexanol (CP 55,940) once per day for 21 consecutive days (150, 200 and 300 μg/kg i.p. for 3, 8 and 10 days, respectively). Following a 21-day drug-free period, working memory was assessed using an object recognition task. Locomotor activity was also measured in the object recognition apparatus via a ceiling-mounted passive infrared sensor. Three days later, anxiety was assessed using a social interaction test. In the object recognition task, significantly poorer working memory was observed in the adolescent but not adult CP 55,940-treated rats. Adolescent, but not adult CP 55,940-treated rats, also exhibited a significant decrease in social interaction with a novel conspecific. These results suggest that chronic exposure to a cannabinoid receptor agonist well after the immediate postnatal period, but before reaching sexual maturity, can lead to increased anxiety and a lasting impairment of working memory.

Using Strawberry Tree WorkbenchMac and Workbench PC software for data acquisition and control in the animal learning laboratory

Publisher: Springer Science and Business Media LLC

Date: 03-1996

DOI: 10.3758/BF03203634

Protein expression profile in the amygdala of rats with methamphetamine-induced behavioral sensitization

Publisher: Elsevier BV

Date: 04-2008

DOI: 10.1016/J.NEULET.2008.02.025

Abstract: Repeated exposure to meth hetamine (MAP) results in a progressively enhanced and enduring behavioral response to the drug. This phenomenon is known as behavioral sensitization. MAP-induced sensitization has been suggested to underlie certain aspects of MAP psychosis and schizophrenia. The mesolimbic dopamine system including the ventral tegmental area, nucleus accumbens (NAc) and associated brain regions such as the amygdala (AMG) are proposed to be involved in the behavioral sensitization. However, the molecular mechanisms underlying this protracted alteration of behavior are almost unknown. Here we examined protein expression profiles in the AMG of acute MAP-treated and MAP-sensitized rats using 2-DE-based proteomics. Analysis revealed that 64 and 43 protein spots were differentially regulated in the AMG of acute MAP-treated and MAP-sensitized rats, respectively, when compared to control rats. A total of 48 and 34 proteins were identified in these two models, respectively using MALDI-ToF-MS. When the results were compared between acute and chronic MAP-treated groups, only 9 proteins were identified in common. These proteins could be related to acute MAP effects and/or non-specific effects. It is therefore suggested that AMG react differently to the acute and repeated administration of MAP at least at the protein expression level. A number of proteins in the categories of synaptic, cytoskeletal, oxidative stress, apoptosis, and mitochondria related proteins were differentially expressed in the AMG of sensitized animals. Changes of these protein expressions in the AMG could be associated with the mechanism underlying behavioral sensitization.

The dopamine receptor antagonist SCH 23390 attenuates feeding induced by Δ ⁹-tetrahydrocannabinol

Publisher: Elsevier BV

Date: 09-2004

DOI: 10.1016/J.BRAINRES.2004.06.033

The nonpeptide oxytocin receptor agonist WAY 267,464: receptor-binding profile, prosocial effects and distribution of c-Fos expression in adolescent rats.

Publisher: Wiley

Date: 19-06-2012

DOI: 10.1111/J.1365-2826.2012.02311.X

Trends in the utilisation of psychotropic medications in Australia from 2000 to 2011

Publisher: SAGE Publications

Date: 09-11-2013

DOI: 10.1177/0004867412466595

Abstract: This study examined longitudinal trends in the dispensing of psychotropic medications in Australia from January 2000 to December 2011. Dispensing data for the major classes of psychotropic medications (antidepressants, anxiolytics, sedatives, antipsychotics, mood stabilisers and attention-deficit hyperactivity disorder (ADHD) medications) were obtained from the Drug Utilisation Sub-Committee of the Australian Department of Health and Ageing. Results were expressed in terms of defined daily doses/1000 population/day (DDDs/1000/day). There was a 58.2% increase in the dispensing of psychotropic drugs in Australia from 2000 to 2011, driven by major increases in antidepressants (95.3% increase in DDDs/1000/day), atypical antipsychotics (217.7% increase) and ADHD medications (72.9% increase). Dispensing of anxiolytics remained largely unchanged, while sedatives and typical antipsychotics decreased by 26.4% and 61.2%, respectively. Lithium dispensing remained static while valproate and lamotrigine increased markedly. In 2011, antidepressants accounted for 66.9% of total psychotropic DDDs/1000/day totals, far greater than anxiolytics (11.4%), antipsychotics (7.3%), mood stabilisers (5.8%), sedatives (5.5%), or ADHD medications (3.0%). Sertraline, olanzapine, valproate and methylphenidate were the most frequently dispensed antidepressant, antipsychotic, mood stabiliser and ADHD medication, respectively, while diazepam and temazepam were the most commonly dispensed anxiolytic and sedative. Psychotropic utilisation markedly increased in Australia between 2000 and 2011. Some potential concerns include: (1) the continuing high use of benzodiazepines, particularly alprazolam, despite their problematic effects (2) the rapid increase in serotonin noradrenaline reuptake inhibitor (SNRI) use, given their more complex side-effect profile relative to selective serotonin reuptake inhibitors (SSRIs) and (3) the dramatic increase in antidepressant prescriptions despite questions about the efficacy of these drugs in mild to moderate depression. Finally, some limitations are identified regarding use of the DDDs/1000/day metric, which can distort estimates of utilisation of specific drugs when the defined daily dose is higher or lower than the formulation most commonly dispensed by pharmacies.

The major plant-derived cannabinoid ⁹-tetrahydrocannabinol promotes hypertrophy and macrophage infiltration in adipose tissue

Publisher: Georg Thieme Verlag KG

Date: 21-12-2012

DOI: 10.1055/S-0031-1297940

Abstract: Synthetic cannabinoid receptor agonists activate lipoprotein lipase and the formation of lipid droplets in cultured adipocytes. Here we extend this work by examining whether Δ(9)-tetrahydrocannabinol (THC), a major plant-derived cannabinoid, increases adipocyte size in vivo. Further, possibly as a consequence of hypertrophy, we hypothesize that THC exposure promotes macrophage infiltration into adipose tissue, an inflammatory state observed in obese in iduals. Rats repeatedly exposed to THC in vivo had reduced body weight, fat pad weight, and ingested less food over the drug injection period. However, THC promoted adipocyte hypertrophy that was accompanied by a significant increase in cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) expression, an enzyme important in packaging triglycerides. We also showed that THC induced macrophage infiltration and increased expression of the inflammatory cytokine tumor necrosis factor alpha (TNF-α) in adipose tissue but did not induce apoptosis as measured by TUNEL staining. That THC increased adipocyte cell size in the absence of greater food intake, body weight and fat provides a unique model to explore mechanisms underlying changes in adipocyte size associated with a mild inflammatory state in fat tissue.

Synthesis and pharmacology of new psychoactive substance 5F-CUMYL-P7AICA, a scaffold- hopping analog of synthetic cannabinoid receptor agonists 5F-CUMYL-PICA and 5F-CUMYL-PINACA

Publisher: Wiley

Date: 10-2019

DOI: 10.1002/DTA.2491

Abstract: Synthetic cannabinoid receptor agonists (SCRAs) are a dynamic class of new psychoactive substances (NPS), with novel chemotypes emerging each year. Following the putative detection of 5F-CUMYL-P7AICA in Australia in 2016, the scaffold-hopping SCRAs 5F-CUMYL-PICA, 5F-CUMYL-PINACA, and 5F-CUMYL-P7AICA were synthesized and characterized by nuclear magnetic resonance (NMR) spectroscopy, gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-quadrupole time-of-flight-MS (LC-QTOF-MS). Since little is known of the pharmacology of 7-azaindole SCRAs like 5F-CUMYL-P7AICA, the binding affinities and functional activities of all compounds at cannabinoid type 1 and type 2 receptors (CB

Altered behaviour and cognitive function following combined deletion of Toll-like receptors 2 and 4 in mice

Publisher: Elsevier BV

Date: 04-2016

DOI: 10.1016/J.BBR.2016.01.024

Abstract: Activation of the immune system due to infection or aging is increasingly linked to impaired neuropsychological function. Toll-like receptors 2 and 4 (TLR2, TLR4) are well-characterised for their role in inflammatory events, and their combined activation has been implicated in neurological diseases. We therefore determined whether TLR2 and TLR4 double gene knockout (GKO) mice showed modified behaviour and cognitive function during a 16-day test sequence that employed the automated IntelliCage test system. The IntelliCage features a home cage environment in which groups of mice live and where water reward is gained through performing various tasks centred on drinking stations in each corner of the apparatus. All mice were tested twice, one month apart (the first sequence termed "R1"and the second "R2"). There were fewer corner visits and nosepokes in TLR2/4 GKO compared to wild-type mice during early exploration in R1, suggesting elevated neophobia in GKO mice. Reduced exploration persisted over subsequent test modules during the dark phase. TLR2/4 GKO mice also displayed increased corner visits during drinking sessions compared to non-drinking sessions, but this was not associated with increased drinking. In subsequent, more complex test modules, TLR2/4 GKO mice had unimpaired spatial learning, but showed markedly poorer performance in a visual discrimination reversal task compared to wild-type mice. These results indicated subtle impairments in behaviour and cognitive functions due to double deficiency in TLR2 and TLR4. These finding are highly relevant to understanding the combined actions of TLR2 and TLR4 on neurological status in a range of different disease conditions.

Randomised Controlled Trial (RCT) of cannabinoid replacement therapy (Nabiximols) for the management of treatment-resistant cannabis dependent patients: A study protocol

Publisher: Springer Science and Business Media LLC

Date: 18-05-2018

DOI: 10.1186/S12888-018-1682-2

Erratum to: In vitro and in vivo pharmacokinetics and metabolism of synthetic cannabinoids CUMYL-PICA and 5F-CUMYL-PICA

Publisher: Springer Science and Business Media LLC

Date: 08-2017

DOI: 10.1007/S11419-017-0380-Y

Heterozygous neuregulin 1 mice display greater baseline and Δ9-tetrahydrocannabinol-induced c-Fos expression

Publisher: Elsevier BV

Date: 11-2007

DOI: 10.1016/J.NEUROSCIENCE.2007.08.020

Abstract: Cannabis use may increase the risk of developing schizophrenia by precipitating the disorder in genetically vulnerable in iduals. Neuregulin 1 (NRG1) is a schizophrenia susceptibility gene and mutant mice heterozygous for the transmembrane domain of this gene (Nrg1 HET mice) exhibit a schizophrenia-related phenotype. We have recently shown that Nrg1 HET mice are more sensitive to the behavioral effects of the main psychoactive constituent of cannabis, Delta(9)-tetrahydrocannabinol (THC). In the present study, we examined the effects of THC (10 mg/kg i.p.) on neuronal activity in Nrg1 HET mice and wild type-like (WT) mice using c-Fos immunohistochemistry. In the lateral septum, THC selectively increased c-Fos expression in Nrg1 HET mice with no corresponding effect being observed in WT mice. In addition, THC promoted a greater increase in c-Fos expression in Nrg1 HET mice than WT mice in the central nucleus of the amygdala, the bed nucleus of the stria terminalis and the paraventricular nucleus of the hypothalamus. Consistent with Nrg1 HET mice exhibiting a schizophrenia-related phenotype, these mice expressed greater drug-free levels of c-Fos in two regions thought to be involved in schizophrenia, the shell of the nucleus accumbens and the lateral septum. Interestingly, the effects of genotype on c-Fos expression, drug-free or following THC exposure, were only observed when animals experienced behavioral testing prior to perfusion. This suggests an interaction with stress was necessary for the promotion of these effects. These data provide neurobiological correlates for the enhanced behavioral sensitivity of Nrg1 HET mice to THC and reinforce the existence of cannabinoid-neuregulin 1 interactions in the CNS. This research may enhance our understanding of how genetic factors increase in idual vulnerability to schizophrenia and cannabis-induced psychosis.

Lithium carbonate in the management of cannabis withdrawal: a randomized placebo-controlled trial in an inpatient setting

Publisher: Springer Science and Business Media LLC

Date: 06-2014

DOI: 10.1007/S00213-014-3611-5

Abstract: Preclinical studies suggest that lithium carbonate (lithium) can reduce precipitated cannabinoid withdrawal in rats by stimulating release of the neuropeptide oxytocin, while two open-label studies indicate lithium may ameliorate cannabis withdrawal symptoms in humans. This study was conducted to examine the efficacy and safety of lithium in the inpatient management of cannabis withdrawal and to determine whether lithium affects plasma oxytocin and the rate of elimination of plasma cannabinoids during abstinence. Treatment-seeking cannabis-dependent adults (n = 38) were admitted for 8 days to an inpatient withdrawal unit and randomized to either oral lithium (500 mg) or placebo given twice a day under double-blind randomized controlled trial (RCT) conditions. Primary outcomes included withdrawal severity [cannabis withdrawal scale (CWS)], rates of detoxification completion, and adverse events. Plasma cannabinoids, plasma oxytocin and serum lithium levels were measured repeatedly over admission. Follow-up research interviews were conducted at 14, 30, and 90 days postdischarge. Lithium did not significantly affect total CWS scores relative to placebo, although it significantly reduced in idual symptoms of "loss of appetite," "stomach aches," and "nightmares/strange dreams." No significant group differences were found in treatment retention or adverse events. Lithium did not increase plasma oxytocin levels nor influence the rate of elimination of cannabinoids. Both placebo- and lithium-treated participants showed reduced levels of cannabis use (verified by urinalysis) and improved health and psychosocial outcomes at 30- and 90-day follow-up relative to pretreatment baselines. Despite the strong rationale for the present study, the efficacy of lithium over placebo in the management of cannabis withdrawal was not demonstrated.

Beer promotes high levels of alcohol intake in adolescent and adult alcohol-preferring rats

Publisher: Elsevier BV

Date: 08-2011

DOI: 10.1016/J.ALCOHOL.2010.12.007

Abstract: Previous studies suggest that high levels of alcohol consumption can be obtained in laboratory rats by using beer as a test solution. The present study extended these observations to examine the intake of beer and equivalent dilute ethanol solutions with an inbred line of alcohol-preferring P rats. In Experiment 1, male adolescent P rats and age-matched Wistar rats had access to either beer or equivalent ethanol solutions for 1h daily in a custom-built lickometer apparatus. In subsequent experiments, adolescent (Experiment 2) and adult (Experiment 3) male P rats were given continuous 24-h home cage access to beer or dilute ethanol solutions, with concomitant access to lab chow and water. In each experiment, the alcohol content of the beer and dilute ethanol solutions was gradually increased from 0.4, 1.4, 2.4, 3.4, 4.4, 5 to 10% EtOH (vol/vol). All three experiments showed a major augmentation of alcohol intake when rats were given beer compared with equivalent ethanol solutions. In Experiment 1, the overall intake of beer was higher in P rats compared with Wistar rats, but no strain difference was found during the 1-h sessions with plain ethanol consumption. Experiment 1 also showed that an alcohol deprivation effect was more readily obtained in rats with a history of consuming beer rather than plain ethanol solutions. In Experiments 2 and 3, voluntary beer intake in P rats represented ethanol intake of 10-15 g/kg/day, among the highest reported in any study with rats. This excessive consumption was most apparent in adolescent rats. Beer consumption markedly exceeded plain ethanol intake in these experiments except at the highest alcohol concentration (10%) tested. The advantage of using beer rather than dilute ethanol solutions in both selected and nonselected rat strains is therefore confirmed. Our findings encourage the use of beer with alcohol-preferring rats in future research that seeks to obtain high levels of alcohol self-administration.

Pharmacology of Indole and Indazole Synthetic Cannabinoid Designer Drugs AB-FUBINACA, ADB-FUBINACA, AB-PINACA, ADB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, ADBICA, and 5F-ADBICA

Publisher: American Chemical Society (ACS)

Date: 17-07-2015

DOI: 10.1021/ACSCHEMNEURO.5B00112

Abstract: Synthetic cannabinoid (SC) designer drugs based on indole and indazole scaffolds and featuring l-valinamide or l-tert-leucinamide side chains are encountered with increasing frequency by forensic researchers and law enforcement agencies and are associated with serious adverse health effects. However, many of these novel SCs are unprecedented in the scientific literature at the time of their discovery, and little is known of their pharmacology. Here, we report the synthesis and pharmacological characterization of AB-FUBINACA, ADB-FUBINACA, AB-PINACA, ADB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, ADBICA, 5F-ADBICA, and several analogues. All synthesized SCs acted as high potency agonists of CB1 (EC50 = 0.24-21 nM) and CB2 (EC50 = 0.88-15 nM) receptors in a fluorometric assay of membrane potential, with 5F-ADB-PINACA showing the greatest potency at CB1 receptors. The cannabimimetic activities of AB-FUBINACA and AB-PINACA in vivo were evaluated in rats using biotelemetry. AB-FUBINACA and AB-PINACA dose-dependently induced hypothermia and bradycardia at doses of 0.3-3 mg/kg, and hypothermia was reversed by pretreatment with a CB1 (but not CB2) antagonist, indicating that these SCs are cannabimimetic in vivo, consistent with anecdotal reports of psychoactivity in humans.

Medical cannabis use in the Australian community following introduction of legal access: the 2018–2019 Online Cross-Sectional Cannabis as Medicine Survey (CAMS-18)

Publisher: Springer Science and Business Media LLC

Date: 08-06-2020

DOI: 10.1186/S12954-020-00377-0

Abstract: In 2016, the Australian federal government passed legislation enabling a range of cannabis-based products to be prescribed to patients by registered healthcare professionals. An online survey conducted immediately prior to these legislative changes found that the vast majority of respondents at the time were illicitly sourcing cannabis plant matter, smoking was the preferred route of administration and mental health, chronic pain, and sleep conditions were the most frequently cited reasons for medical cannabis use. This manuscript reports the results of a follow-up survey conducted in 2018–2019, the Cannabis As Medicine Survey (CAMS-18). The goal of this second questionnaire was to examine patterns of use and consumer perspectives regarding medical cannabis use in Australia, 2 years after the introduction of legal access pathways. Anonymous online cross-sectional survey with convenience s le, recruited mainly through online media between September 2018 and March 2019. Participants were adults (18 years or over) residing in Australia who reported using a cannabis product for self-identified therapeutic reasons during the preceding 12 months. The survey measured consumer characteristics, indications and patterns of medical cannabis use, routes and frequency of administration, perceived benefits and harms, experiences and preferred models of access to medical cannabis. Data were available for 1388 respondents. The main categories of condition being treated with medical cannabis were pain (36.4%), mental health (32.8%), sleep (9.2%), neurological (5.2%) and cancer (3.8%). Respondents reported using medical cannabis on 15.8 (11.2) days in the past 28, by inhaled (71.4%) or oral (26.5%) routes and spending AUD$82.27 ($101.27) per week. There were high levels of self-reported effectiveness, but also high rates of side effects. There was uncertainty regarding the composition of illicit cannabinoid products and concerns regarding their possible contamination. Few respondents (2.7%) had accessed legally prescribed medical cannabis, with the main perceived barriers being cost, disinterest from the medical profession and stigma regarding cannabis use. Chronic pain, mental health and sleep remain the main clinical conditions for which consumers report using medical cannabis. Despite 2 years of legal availability, most consumers in Australia reported accessing illicit cannabis products, with uncertainty regarding the quality or composition of cannabis products.

Cat odor, but not trimethylthiazoline (fox odor), activates accessory olfactory and defense-related brain regions in rats

Publisher: Elsevier BV

Date: 02-2008

DOI: 10.1016/J.NEUROSCIENCE.2007.11.039

Abstract: Cat odor and trimethylthiazoline (TMT, a component of fox feces) are two stimuli widely used in rodent models of fear and anxiety. Recent studies suggest that these odorants have distinct behavioral effects, raising questions as to whether TMT is a true "predator odor." Here we used c-Fos immunohistochemistry to compare patterns of neural activation produced by cat odor and TMT. Rats were exposed to either (1) three pieces of a collar that had been worn by a domestic cat, (2) three collar pieces impregnated with TMT (30 microl iece), (3) three collar pieces impregnated with 4% formaldehyde (200 microl iece, an acrid but non-predatory odor), or (4) three control (no odor) collar pieces. Odors were presented in a small well-ventilated plastic box. All odorants (cat odor, TMT and formaldehyde) produced increased defecation in rats compared with the control group, and formaldehyde exposure also decreased rearing. Cat odor increased contact with the stimulus relative to all other groups, while TMT increased contact compared with the formaldehyde and clean air groups. Only cat odor decreased grooming and elicited escape attempts. In addition, only cat odor caused pronounced activation of Fos in the accessory olfactory bulb and its projection areas, anterior olfactory nucleus, medial prefrontal cortex, striatum, and a medial hypothalamic circuit associated with defensive behavior. In contrast, the only areas activated by TMT were the internal granular layer of the main olfactory bulb and central amygdala, while both cat odor and TMT activated the glomeruli of the main olfactory bulb, piriform cortex, ventral orbital cortex and anterior cortical amygdala. Results indicate that the effects of cat odor and TMT are easily distinguished both behaviorally and at a neural level, and suggest that TMT lacks the "pheromone-like" quality of cat odor that engages key hypothalamic sites involved in defensive behavior.

The schizophrenia susceptibility gene neuregulin 1 modulates tolerance to the effects of cannabinoids

Publisher: Oxford University Press (OUP)

Date: 12-08-2010

DOI: 10.1017/S146114571000091X

The chemistry and pharmacology of synthetic cannabinoid SDB-006 and its regioisomeric fluorinated and methoxylated analogs

Publisher: Wiley

Date: 23-02-2018

DOI: 10.1002/DTA.2362

Abstract: Synthetic cannabinoids are the largest and most structurally erse class of new psychoactive substances, with manufacturers often using isomerism to evade detection and circumvent legal restriction. The regioisomeric methoxy- and fluorine-substituted analogs of SDB-006 (N-benzyl-1-pentyl-1H-indole-3-carboxamide) were synthesized and could not be differentiated by gas chromatography-mass spectrometry (GC-MS), but were distinguishable by liquid chromatography-quadrupole time-of-flight-MS (LC-QTOF-MS). In a fluorescence-based plate reader membrane potential assay, SDB-006 acted as a potent agonist at human cannabinoid receptors (CB

Chronic Methamphetamine Self‐Administration Dysregulates Oxytocin Plasma Levels and Oxytocin Receptor Fibre Density in the Nucleus Accumbens Core and Subthalamic Nucleus of the Rat

Publisher: Wiley

Date: 04-2016

DOI: 10.1111/JNE.12337

Abstract: The neuropeptide oxytocin attenuates reward and abuse for the psychostimulant meth hetamine (METH). Recent findings have implicated the nucleus accumbens (NAc) core and subthalamic nucleus (STh) in oxytocin modulation of acute METH reward and relapse to METH-seeking behaviour. Surprisingly, the oxytocin receptor (OTR) is only modestly involved in both regions in oxytocin attenuation of METH-primed reinstatement. Coupled with the limited investigation of the role of the OTR in psychostimulant-induced behaviours, we primarily investigated whether there are cellular changes to the OTR in the NAc core and STh, as well as changes to oxytocin plasma levels, after chronic METH i.v. self-administration (IVSA) and after extinction of drug-taking. An additional aim was to examine whether changes to central corticotrophin-releasing factor (CRF) and plasma corticosterone levels were also apparent because of the interaction of oxytocin with stress-regulatory mechanisms. Male Sprague-Dawley rats were trained to lever press for i.v. METH (0.1 mg/kg/infusion) under a fixed-ratio 1 schedule or received yoked saline infusions during 2-h sessions for 20 days. An additional cohort of rats underwent behavioural extinction for 15 days after METH IVSA. Subsequent to the last day of IVSA or extinction, blood plasma was collected for enzyme immunoassay, and immunofluorescence was conducted on NAc core and STh coronal sections. Rats that self-administered METH had higher oxytocin plasma levels, and decreased OTR-immunoreactive (-IR) fibres in the NAc core than yoked controls. In animals that self-administered METH and underwent extinction, oxytocin plasma levels remained elevated, OTR-IR fibre density increased in the STh, and a trend towards normalisation of OTR-IR fibre density was evident in the NAc core. CRF-IR fibre density in both brain regions and corticosterone plasma levels did not change across treatment groups. These findings demonstrate that oxytocin systems, both centrally within the NAc core and STh, as well as peripherally through plasma measures, are dysregulated after METH abuse.

Cannabidiol treatment reduces the motivation to self-administer methamphetamine and methamphetamine-primed relapse in rats

Publisher: SAGE Publications

Date: 27-09-2018

DOI: 10.1177/0269881118799954

Abstract: Meth hetamine is an addictive stimulant that can cause many adverse physical, psychological and psychosocial effects. Preliminary evidence shows cannabidiol, a non-intoxicating constituent of the cannabis plant, may have efficacy in treating opioid and nicotine dependence. However, no study has yet examined whether cannabidiol treatment might impact on meth hetamine addiction. The current study investigated whether cannabidiol administration reduces the motivation to self-administer meth hetamine and relapse to meth hetamine-seeking behavior following abstinence. Thirty-two male Sprague Dawley rats with implanted jugular vein catheters were initially trained to self-administer meth hetamine via lever press during two-hour sessions on a fixed ratio 1 schedule of reinforcement. Rats in experiment 1 ( n=16) then advanced to a progressive ratio reinforcement schedule to examine the effects of cannabidiol (0, 20, 40, and 80 mg/kg intraperitoneal) on motivation to self-administer meth hetamine. Rats in experiment 2 ( n=16) were tested for cannabidiol effects on meth hetamine-primed reinstatement following extinction. Cannabidiol (80 mg/kg, but not 40 mg/kg, or 20 mg/kg) reduced the motivation to self-administer meth hetamine and attenuated meth hetamine-primed relapse to meth hetamine-seeking behavior after extinction. This is the first demonstration that cannabidiol can reduce the motivation to seek and consume meth hetamine, and suggests that cannabidiol might be worth trialing as a novel pharmacotherapy for meth hetamine dependence.

Behavioral and cognitive data in mice with different tryptophan-metabolizing enzymes knocked out

Publisher: Elsevier BV

Date: 12-2016

DOI: 10.1016/J.DIB.2016.08.071

A Meta‐Analysis on the Impact of Alcohol Dependence on Short‐Term Resting‐State Heart Rate Variability: Implications for Cardiovascular Risk

Publisher: Wiley

Date: 26-07-2012

DOI: 10.1111/J.1530-0277.2012.01913.X

Abstract: Alcohol dependence is associated with an increased likelihood of cardiac events. Reductions in heart rate variability (HRV) may be one mechanism linking dependence with these events. HRV may also be related to poor social functioning and the lack of impulse control commonly observed in alcohol-dependent in iduals. However, prior studies on the impact of alcohol dependence on HRV have reported contradictory findings highlighting the need for a meta-analysis. Studies comparing short-term HRV in alcohol-dependent populations and healthy controls who were nondependent were considered for meta-analysis. Only studies reporting findings from participants without cardiovascular disease were included in the analysis. Meta-analyses were based on 6 articles that fulfilled inclusion criteria, comprising a total of 177 alcohol-dependent participants and 216 nondependent participants. Alcohol-dependent participants displayed reduced HRV (Hedges' g = -0.6, p > 0.001) in comparison with nondependent participants. No differences were observed between the summary effect sizes obtained from different HRV domains (Q = 1.19, p = 0.55). Alcohol dependence is associated with reduced HRV, an effect associated with a medium effect size. Findings highlight the importance of monitoring alcohol-dependent patients for cardiac disease and emphasize the need for cardiovascular risk reduction strategies in these patients.

Residual social, memory and oxytocin-related changes in rats following repeated exposure to γ-hydroxybutyrate (GHB), 3,4- methylenedioxymethamphetamine (MDMA) or their combination

Publisher: Springer Science and Business Media LLC

Date: 21-08-2010

DOI: 10.1007/S00213-010-1986-5

Abstract: There has been little investigation of the possible lasting adverse effects of γ-hydroxybutyrate (GHB). This study aims to study whether GHB produces residual adverse effects on memory and social behaviour in rats and lasting changes in brain monoamines and oxytocin-related gene expression. Rats received daily intraperitoneal injections of GHB (500 mg/kg), methylenedioxymeth hetamine (MDMA 5 mg/kg) or their combination (GHB/MDMA) over ten consecutive days. Locomotor activity and body weight were assessed during the dosing period and withdrawal-related anxiety was assessed 24 h after drug cessation. After a washout of 4 weeks, rats were tested on the emergence, social interaction, and object recognition tasks over a 2-week period. Monoamine levels in cortex and striatum, and hypothalamic oxytocin and oxytocin receptor mRNA, were then assessed. MDMA and GHB/MDMA caused modest sensitization of locomotor activity over time, while sedative effects of GHB diminished with repeated exposure. GHB-treated rats showed reduced social interaction 24 h after the final dose, indicating GHB withdrawal-induced anxiety. All drug-treated groups displayed residual deficits in social interaction and object recognition. No changes in monoamine levels were detected 8 weeks post-drug. However, MDMA pre-exposure increased hypothalamic oxytocin mRNA while GHB pre-exposure upregulated oxytocin receptor mRNA. GHB/MDMA pre-exposure caused intermediate changes in both of these measures. GHB treatment caused residual impairments in memory and social behaviour and increases in anxiety, paralleling the lasting adverse effects of MDMA. Both drugs caused lasting neuroadaptations in brain oxytocin systems and this may be related to the long-term social interaction deficiencies caused by both drugs.

Modulation of morphine-induced Fos-immunoreactivity by the cannabinoid receptor antagonist SR 141716

Publisher: Elsevier BV

Date: 12-2004

DOI: 10.1016/J.NEUROPHARM.2004.08.008

Abstract: A growing body of evidence suggests the existence of a functional interaction between opioid and cannabinoid systems. The present study further investigated this functional interaction by examining the combined effects of morphine and the cannabinoid receptor antagonist SR 141716 on Fos-immunoreactivity (Fos-IR), a marker for neural activation. Male albino Wistar rats were treated with SR 141716 (3 mg/kg, intraperitoneally), morphine HCl (10 mg/kg, subcutaneously), vehicle, or SR 141716 and morphine combined (n = 6 per group). Rats were injected with morphine or its vehicle 30-min after administration of SR 141716 or its vehicle and perfused 3 h later. Locomotor activity and body temperature were both increased in the morphine-treated group and SR 141716 significantly inhibited these effects. Morphine increased Fos-IR in several brain regions including the caudate-putamen (CPu), cortex (cingulate, insular and piriform), nucleus accumbens (NAS) shell, lateral septum (LS), bed nucleus of the stria terminalis (BNST), median preoptic nucleus (MnPO), medial preoptic nucleus (MPO), hypothalamus (paraventricular, dorsomedial and ventromedial), paraventricular thalamic nucleus (PV), amygdala (central and basolateral nuclei), dorsolateral periaqueductal gray, ventral tegmental area (VTA), and Edinger-Westphal nucleus. SR 141716 alone increased Fos-IR in the cortex (cingulate, insular and piriform), NAS (shell), LS, BNST, hypothalamus (paraventricular, dorsomedial and ventromedial), PV, amygdala (central, basolateral and medial nuclei), VTA, and Edinger-Westphal nucleus. SR 141716 attenuated morphine-induced Fos-IR in several regions including the CPu, cortex, NAS (shell), LS, MnPO, MPO, paraventricular and dorsomedial hypothalamus, PV, basolateral amygdala, VTA, and Edinger-Westphal nucleus (EW). These results provide further support for functional interplay between the cannabinoid and opioid systems. Possible behavioural and physiological implications of the interactive effects of SR 141716 on morphine-induced Fos-IR are discussed.

A behavioural comparison of acute and chronic ⁹- tetrahydrocannabinol and cannabidiol in C57BL/6JArc mice

Publisher: Oxford University Press (OUP)

Date: 29-09-2010

DOI: 10.1017/S1461145709990605

Cocaine and heroin ('speedball') self-administration: The involvement of nucleus accumbens dopamine and ?-opiate, but not ?-opiate receptors

Publisher: Springer Science and Business Media LLC

Date: 29-01-2005

DOI: 10.1007/S00213-004-2135-9

Abstract: The combined administration of heroin and cocaine ('speedball') is common among intravenous drug users. Dopamine receptors in the nucleus accumbens play a key role in cocaine self-administration however, their role in speedball self-administration is unknown, as is the role of opiate receptors in this region. The effect of blocking dopamine D1, D2, mu-opiate or delta-opiate receptors in the nucleus accumbens on the intravenous self-administration of combined heroin and cocaine was examined in rats. Rats with bilateral cannulae implanted into the nucleus accumbens were trained to self-administer intravenous speedball (ratio of cocaine/heroin, 17:1) under a progressive ratio (PR) schedule. Prior to their self-administration session, rats were then microinjected with the dopamine D1 receptor antagonist SCH 23390 (1 and 6 nmol side(-1)), the D2 receptor antagonist raclopride (3 and 10 nmol side(-1)), the mu-opiate receptor antagonist CTOP (0.1, 0.3 and 1.0 nmol side(-1)), the delta-opiate receptor antagonist naltrindole (1.0, 3.0 and 10 nmol side(-1)) or a cocktail of SCH 23390 (1 nmol side(-1)) and CTOP (0.1 nmol side(-1)) into the nucleus accumbens. Microinjection of SCH 23390, raclopride or CTOP into the nucleus accumbens produced dose-dependent decreases in breakpoints under the PR schedule, while naltrindole was without effect. The highest dose of SCH 23390 also significantly reduced locomotor activity measured during speedball self-administration. The combination of SCH 23390 and CTOP significantly reduced breakpoints, while not affecting locomotor activity. These results indicate that dopamine and mu-opiate receptors, but not delta-opiate receptors, in the nucleus accumbens are involved in the reinforcing effects of speedball. Combined administration of D1 and mu-opiate receptor antagonists may be more selective at reducing the reinforcing effects of speedball self-administration than either drug alone.

Driving on ice: impaired driving skills in current methamphetamine users

Publisher: Springer Science and Business Media LLC

Date: 29-07-2012

DOI: 10.1007/S00213-012-2805-Y

Abstract: Previous research indicates a complex link between meth hetamine (METH) and driving performance. Acute dosing with hetamines has improved driving-related performance in some laboratory studies, while epidemiological studies suggest an association between METH use, impaired driving, and accident culpability. Current METH users were compared to a control group of nonusers on driving simulator performance. Groups were matched for age, gender, and driving experience. Subjects were assessed for current drug use, drug dependence, and drug levels in saliva/blood as well as personality variables, sleepiness, and driving performance. METH users, most of whom met the criteria for METH dependence, were significantly more likely to speed and to weave from side to side when driving. They also left less distance between their vehicle and oncoming vehicles when making a right-hand turn. This risky driving was not associated with current blood levels of METH or its principal metabolite, hetamine, which varied widely within the METH group. Other drugs were detected (principally low levels of THC or MDMA) in some METH users, but at levels that were unlikely to impair driving performance. There were higher levels of impulsivity and antisocial personality disorder in the METH-using cohort. These findings confirm indications from epidemiological studies of an association between METH use and impaired driving ability and provide a platform for future research to further explore the factors contributing to increased accident risk in this population.

Effects of typical (haloperidol) and atypical (risperidone) antipsychotic agents on protein expression in rat neural stem cells

Publisher: Elsevier BV

Date: 12-2009

DOI: 10.1016/J.NEUINT.2009.05.007

Abstract: Neural stem cells (NSCs) play a crucial role in the development and maturation of the central nervous system. Recently studies suggest that antipsychotic drugs regulate the activities of NSCs. However, the molecular mechanisms underlying antipsychotic-induced changes of the activity of NSCs, particularly protein expression, are still unknown. We studied the growth and protein expression in haloperidol (HD) and risperidone (RS) treated rat NSCs. The treatment with RS (3microM) or HD (3microM) had no effect on morphology of NSCs after 24h, but significantly promotes or inhibits the differentiation of NSCs after a 96h of treatment. 2-DE based proteomics was performed at 24h, a stage before phenotypic expression of NSCs. Gel image analysis revealed that 30 protein spots in HD- and 60 spots in RS-treated groups were differentially regulated in their expression compared to control group (p<0.05 ANOVA). When these spots were compared between the two drug-treated groups, 23 spots overlapped leaving 7 HD-specific and 37 RS-specific spots. Of these 67 spots, 32 different proteins were identified. The majority of the differentially regulated proteins were classified into several functional groups, such as cytoskeletal, calcium regulating protein, metabolism, signal transduction and proteins related to oxidative stress. Our data shows that atypical RS expressed more proteins than typical HD, and these results might explain the molecular mechanisms underlying the different effects of both drugs on NSCs activities as described above. Identified proteins in this experiment may be useful in future studies of NSCs differentiation and/or understanding in molecular mechanisms of different neural diseases including schizophenia.

Molecular and Behavioral Pharmacological Characterization of Abused Synthetic Cannabinoids MMB- and MDMB-FUBINACA, MN-18, NNEI, CUMYL-PICA, and 5-Fluoro-CUMYL-PICA

Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)

Date: 16-03-2018

DOI: 10.1124/JPET.117.246983

MDMA (‘Ecstasy’), oxytocin and vasopressin modulate social preference in rats: A role for handling and oxytocin receptors

Publisher: Elsevier BV

Date: 11-2016

DOI: 10.1016/J.PBB.2016.10.002

Abstract: In laboratory rats, peripheral administration of the neuropeptides oxytocin (OT) and vasopressin (AVP) induces similar prosocial effects (i.e. increased adjacent lying) to the party drug 3,4-methylenedioxymeth hetamine (MDMA), which are sensitive to vasopressin V

MDMA-induced c-Fos expression in oxytocin-containing neurons is blocked by pretreatment with the 5-HT-1A receptor antagonist WAY 100635

Publisher: Elsevier BV

Date: 08-2011

DOI: 10.1016/J.BRAINRESBULL.2011.06.011

Abstract: The popular party drug MDMA (3,4-methylenedioxymeth hetamine, "Ecstasy") increases sociability in both humans and laboratory animals. Recent research suggests that these prosocial effects may involve serotonin (5-HT)-stimulated hypothalamic release of the neuropeptide oxytocin. WAY 100635, a 5-HT(1A) receptor antagonist, prevents MDMA-induced increases in plasma oxytocin and also reduces MDMA-mediated increases in social interaction in rats. The present study used c-Fos immunohistochemistry to determine the possible role of 5-HT(1A) receptors in MDMA-mediated activation of oxytocin synthesizing neurons. Male Wistar rats (n=8/group) were administered MDMA (10 mg/kg, i.p.) with or without WAY 100635 (1 mg/kg, i.p.) pre-treatment and c-Fos expression was then assessed throughout the brain. MDMA significantly increased locomotor activity and this effect was partly prevented by WAY 100635, in agreement with previous studies. WAY 100635 significantly reduced MDMA-induced c-Fos expression in a subset of brain regions examined. A particularly prominent reduction was seen in the oxytocin-positive neurons of the supraoptic nucleus and paraventricular hypothalamus, with more modest reductions in the Islands of Calleja, median preoptic nucleus, somatosensory cortex and nucleus of the solitary tract. WAY 100635 did not alter MDMA-induced c-Fos expression in the striatum, thalamus, or central amygdala. These results indicate that MDMA's action on oxytocin producing cells in the hypothalamus is mediated through 5-HT(1A) receptors and that certain specific cortical, limbic and brainstem sites are also activated by MDMA via these receptors.

Pre-exposure to the cannabinoid receptor agonist CP 55,940 enhances morphine behavioral sensitization and alters morphine self-administration in Lewis rats

Publisher: Elsevier BV

Date: 03-2003

DOI: 10.1016/S0014-2999(03)01455-9

Abstract: Three experiments examined the influence of pre-exposure to the cannabinoid receptor agonist CP 55940 ((-)-cis-3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-trans-4-(3-hydroxypropyl)cyclohexanol) on the sensitization of morphine-induced locomotor hyperactivity and self-administration in Lewis rats. In Experiment 1, rats received daily injections of vehicle or CP 55940 (0.1 mg/kg for 7 days then 0.2 mg/kg for a further 7 days). Four weeks later, the locomotor response to morphine (10 mg/kg s.c.) was tested once per day over a 3-h period for 14 consecutive days. Rats given morphine showed hypoactivity during the first hour following morphine but hyperactivity during the second and third hours. A progressive increase in hyperactivity to morphine was seen over the 14 days of administration, which was significantly greater in rats pre-treated with CP 55940. In Experiment 2, rats were given morphine (10 mg/kg) once a day for 14 days in combination with either vehicle, CP 55940 (0.1 mg/kg) or the cannabinoid CB(1) receptor antagonist SR 141716 (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride) (3 mg/kg). Both CP 55940 and SR 141716 initially inhibited the hyperactive response to morphine, but these effects gradually wore off and by the end of 14 days, hyperactivity was similar in all morphine-treated groups. When tested 3 weeks later for their response to morphine (10 mg/kg) given alone, rats previously given the morphine/CP 55940 combination, but not the SR 141716/morphine combination, showed a greater locomotor stimulation than those previously exposed to morphine only. In Experiment 3, rats were pre-exposed to CP 55940 or vehicle for 14 days and were subsequently trained to self-administer morphine intravenously (1 mg/kg per lever press) for 14 days. Rats pre-exposed to CP 55940 self-administered a significantly greater number of morphine infusions than vehicle pre-exposed rats. However, both active and inactive ('dummy') lever presses were increased by cannabinoid pre-treatment. Overall, these results suggest that cannabinoid pre-exposure can lead to an exaggeration of morphine-induced hyperactivity and may alter the reinforcing effects of morphine in Lewis rats. The implications for 'gateway' theories of cannabinoid effects in humans are discussed.

Not all ‘predator odours’ are equal: cat odour but not 2,4,5 trimethylthiazoline (TMT; fox odour) elicits specific defensive behaviours in rats

Publisher: Elsevier BV

Date: 02-2002

DOI: 10.1016/S0166-4328(01)00324-2

Abstract: The behavioural responses to two commonly used 'predator odours' were assessed in male Wistar rats. Cat odour was presented to rats in the form of a piece of collar that had been worn by a domestic cat. Fox odour was presented in an equivalent piece of (unworn) collar that had been impregnated with 2,4,5 Trimethylthiazoline (TMT)-an extract of fox faeces. Other rats were exposed to collars containing Triethylamine (TEA), a putrid fishy smell, or formaldehyde, which has an acrid irritating smell. Experiment 1 showed that rats approached cat odour, TMT and TEA significantly less than they did an unworn collar. However, only cat odour increased retreat to the hide box, reduced locomotor activity and elicited 'head out' behaviour. When tested immediately after odour exposure, only cat odour exposed rats showed increased anxiety in the elevated plus maze and suppressed activity in a 90-min general activity test. When returned to the odour-paired environment 24 h later in the absence of test odours, only rats that had previously received cat odour showed evidence of conditioned fear. Experiment 2 showed that rats given the benzodiazepine drug midazolam (0.5 mg/kg) display increased approach and decreased defensiveness towards a cat odour impregnated collar. In contrast, midazolam accentuated the avoidance of TMT and formaldehyde containing collars. Experiment 3 showed that when cat odour was presented in a small, enclosed environment, rats display increased body immobility, decreased grooming and increased orientation towards the odour-exuding stimulus. These responses were not seen with TMT or TEA containing collars. Taken together, these results suggest that while cat odour strongly elicits specific defensive behaviours in rats, TMT has effects that are more characteristic of an aversive odour. We suggest that the results of some previous studies using TMT may need to be reassessed.

Adolescent rats find repeated Δ⁹-THC less aversive than adult rats but display greater residual cognitive deficits and changes in hippocampal protein expression following exposure

Publisher: Springer Science and Business Media LLC

Date: 20-06-2008

DOI: 10.1038/SJ.NPP.1301475

Abstract: The current study examined whether adolescent rats are more vulnerable than adult rats to the lasting adverse effects of cannabinoid exposure on brain and behavior. Male Wistar rats were repeatedly exposed to Delta-9-tetrahydrocannabinol (Delta(9)-THC, 5 mg/kg i.p.) in a place-conditioning paradigm during either the adolescent (post-natal day 28+) or adult (post-natal day 60+) developmental stages. Adult rats avoided a Delta(9)-THC-paired environment after either four or eight pairings and this avoidance persisted for at least 16 days following the final Delta(9)-THC injection. In contrast, adolescent rats showed no significant place aversion. Adult Delta(9)-THC-treated rats produced more vocalizations than adolescent rats when handled during the intoxicated state, also suggesting greater drug-induced aversion. After a 10-15 day washout, both adult and adolescent Delta(9)-THC pretreated rats showed decreased social interaction, while only Delta(9)-THC pretreated adolescent rats showed significantly impaired object recognition memory. Seventeen days following their last Delta(9)-THC injection, rats were euthanased and hippoc al tissue processed using two-dimensional gel electrophoresis proteomics. There was no evidence of residual Delta(9)-THC being present in blood at this time. Proteomic analysis uncovered 27 proteins, many involved in regulating oxidative stress/mitochondrial functioning and cytoarchitecture, which were differentially expressed in adolescent Delta(9)-THC pretreated rats relative to adolescent controls. In adults, only 10 hippoc al proteins were differentially expressed in Delta(9)-THC compared to vehicle-pretreated controls. Overall these findings suggest that adolescent rats find repeated Delta(9)-THC exposure less aversive than adults, but that cannabinoid exposure causes greater lasting memory deficits and hippoc al alterations in adolescent than adult rats.

Systemically administered oxytocin decreases methamphetamine activation of the subthalamic nucleus and accumbens core and stimulates oxytocinergic neurons in the hypothalamus.

Publisher: Wiley

Date: 23-08-2010

DOI: 10.1111/J.1369-1600.2010.00247.X

Abstract: Recent preclinical evidence indicates that the neuropeptide oxytocin may have potential in the treatment of drug dependence and drug withdrawal. Oxytocin reduces meth hetamine self-administration, conditioned place preference and hyperactivity in rodents. However, it is unclear how oxytocin acts in the brain to produce such effects. The present study examined how patterns of neural activation produced by meth hetamine were modified by co-administered oxytocin. Male Sprague-Dawley rats were pretreated with either 2 mg/kg oxytocin (IP) or saline and then injected with either 2 mg/kg meth hetamine (IP) or saline. After injection, locomotor activity was measured for 80 minutes prior to perfusion. As in previous studies, co-administered oxytocin significantly reduced meth hetamine-induced behaviors. Strikingly, oxytocin significantly reduced meth hetamine-induced Fos expression in two regions of the basal ganglia: the subthalamic nucleus and the nucleus accumbens core. The subthalamic nucleus is of particular interest given emerging evidence for this structure in compulsive, addiction-relevant behaviors. When administered alone, oxytocin increased Fos expression in several regions, most notably in the oxytocin-synthesizing neurons of the supraoptic nucleus and paraventricular nucleus of the hypothalamus. This provides new evidence for central actions of peripheral oxytocin and suggests a self-stimulation effect of exogenous oxytocin on its own hypothalamic circuitry. Overall, these results give further insight into the way in which oxytocin might moderate compulsive behaviors and demonstrate the capacity of peripherally administered oxytocin to induce widespread central effects.

The effect of daily aerobic cycling exercise on sleep quality during inpatient cannabis withdrawal: A randomised controlled trial

Publisher: Wiley

Date: 19-10-2020

DOI: 10.1111/JSR.13211

Proteomic analysis demonstrates adolescent vulnerability to lasting hippocampal changes following chronic alcohol consumption

Publisher: Wiley

Date: 22-12-2009

DOI: 10.1111/J.1530-0277.2008.00814.X

Abstract: Excessive teenage alcohol consumption is of great concern because alcohol may adversely alter the developmental trajectory of the brain. The aim of the present study was to assess whether chronic intermittent alcohol intake during the adolescent period alters hippoc al protein expression to a greater extent than during adulthood. Adolescent [postnatal day (PND) 27] and adult (PND 55) male Wistar rats were given 8 hours daily access to beer (4.44% ethanol v/v) in addition to ad libitum food and water for 4 weeks. From a large subject pool, subgroups of adolescent and adult rats were selected that displayed equivalent alcohol intake (average of 6.1 g/kg/day ethanol). The 4 weeks of alcohol access were followed by a 2-week alcohol-free washout period after which the hippoc us was analyzed using 2-DE proteomics. Beer consumption by the adult group resulted in modest hippoc al changes relative to alcohol naïve adult controls. The only changes observed were an up-regulation of citrate synthase (a precursor to the Krebs cycle) and fatty acid binding protein (which facilitates fatty acid metabolism). In contrast, adolescent rats consuming alcohol showed more widespread hippoc al changes relative to adolescent controls. These included an increase in cytoskeletal protein T-complex protein 1 subunit epsilon (TCP-1) and a decrease in the expression of 10 other proteins, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH), triose phosphate isomerise, alpha-enolase, and phosphoglycerate kinase 1 (all involved in glycolysis) glutamate dehydrogenase 1 (an important regulator of glutamate) methylmalonate-semialdehyde dehydrogenase (involved in aldehyde detoxification) ubiquitin carboxyl-terminal hydrolase isozyme L1 (a regulator of protein degradation) and synapsin 2 (involved in synaptogenesis and neurotransmitter release). These results suggest the adolescent hippoc us is more vulnerable to lasting proteomic changes following repeated alcohol exposure. The proteins most affected include those related to glycolysis, glutamate metabolism, neurodegeneration, synaptic function, and cytoskeletal structure.

University Of Sydney

Location: Australia

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Discovery Projects - Grant ID: DP0667221

Start Date: 01-2006

End Date: 09-2008

Amount: $147,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0988609

Start Date: 01-2009

End Date: 01-2014

Amount: $694,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP160105003

Start Date: 2016

End Date: 12-2019

Amount: $390,400.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0346556

Start Date: 02-2003

End Date: 01-2006

Amount: $121,000.00

Funder: Australian Research Council

Special Research Initiatives - Grant ID: SR0354494

Start Date: 2004

End Date: 02-2004

Amount: $10,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE120100177

Start Date: 08-2012

End Date: 08-2013

Amount: $150,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0989703

Start Date: 07-2010

End Date: 05-2011

Amount: $500,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP0559747

Start Date: 02-2005

End Date: 02-2008

Amount: $225,000.00

Funder: Australian Research Council