ORCID Profile
0000-0002-9754-8069
Current Organisation
Macquarie University
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Central Nervous System | Zoology | Neurogenetics | Biological Psychology (Neuropsychology, Psychopharmacology, Physiological Psychology) | Psychology | Neurobiology
Mental Health | Expanding Knowledge in the Biological Sciences | Expanding Knowledge in Psychology and Cognitive Sciences | Biological sciences |
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.YHBEH.2012.12.003
Abstract: The subthalamic nucleus (STh) is increasingly recognized as an important region involved in the motivation for drug reward. It is not yet known if dopamine, the neurotransmitter primarily responsible for reward signaling, is also involved in mediating reward-related activity in the STh. The neuropeptide oxytocin acts within the STh to reduce the rewarding effects of the psychostimulant meth hetamine, through a proposed interaction with dopamine. However, the mechanisms of this interaction are unclear. The current study aimed to determine whether (i) dopamine microinjected into the STh would result in a significant place preference following a single-trial conditioning session, (ii) co-administered dopamine receptor antagonist would block the formation of a conditioned place preference (CPP) for dopamine, (iii) co-administered oxytocin would prevent CPP for dopamine and (iv) whether the selective oxytocin antagonist desGly-NH(2),d(CH(2))(5)[D-Tyr(2),Thr(4)]OVT, when co-administered with oxytocin and dopamine, would reverse the effects of oxytocin and result in a CPP for dopamine. Results showed that male Sprague Dawley rats i) formed a preference for the context paired with dopamine (100 nmol/side) administration into the STh, which was prevented by co-administration of ii) the mixed dopamine receptor antagonist fluphenazine (10 nmol/side) or iii) oxytocin (0.6 pmol/side), [corrected] with the oxytocin effect on dopamine CPP reversed by the co-administration of the oxytocin receptor antagonist (3 nmol/side). These data suggest that dopamine neurotransmission in the STh produces rewarding effects that can be reduced by activation of local oxytocin receptors.
Publisher: Springer Science and Business Media LLC
Date: 17-05-2022
DOI: 10.1038/S41386-022-01336-Y
Abstract: Early life stress (ELS) is associated with perturbed neural development and augmented vulnerability to mental health disorders, including addiction. How ELS changes the brain to increase addiction risk is poorly understood, and there are no therapies which target this ELS-induced vulnerability. ELS disrupts the oxytocin system, which can modulate addiction susceptibility, suggesting that targeting the oxytocin system may be therapeutic in this ELS-addiction comorbidity. Therefore, we determined whether adolescent oxytocin treatment after ELS could: (1) reduce vulnerability to anxiety, social deficits, and meth hetamine-taking and reinstatement and (2) restore hypothalamic oxytocin and corticotropin-releasing factor expressing neurons and peripheral oxytocin and corticosterone levels. Long Evans pups underwent maternal separation (MS) for either 15 min or 360 min on postnatal days (PND) 1–21. During adolescence (PNDs 28–42), rats received a daily injection of either oxytocin or saline. In Experiment 1, adult rats were assessed using the elevated plus-maze, social interaction procedure, and meth hetamine self-administration procedure, including extinction, and cue-, meth hetamine- and yohimbine-induced reinstatement. In Experiment 2, plasma for enzyme immunoassays and brain tissue for immunofluorescence were collected from adult rats after acute stress exposure. Adolescent oxytocin treatment ameliorated ELS-induced anxiety and reduced meth hetamine- and yohimbine-induced reinstatement in both sexes, and suppressed meth hetamine intake and facilitated extinction in males only. Additionally, adolescent oxytocin treatment after ELS restored oxytocin-immunoreactive cells and stress-induced oxytocin levels in males, and attenuated stress-induced corticosterone levels in both sexes. Adolescent oxytocin treatment reverses some of the ELS effects on later-life psychopathology and vulnerability to addiction.
Publisher: Springer Science and Business Media LLC
Date: 03-08-2022
DOI: 10.1007/S00213-022-06175-9
Abstract: Meth hetamine (METH, “ice”) is a potent and addictive psychostimulant. Abuse of METH perturbs neurotransmitter systems and induces neurotoxicity however, the neurobiological mechanisms which underlie addiction to METH are not fully understood, limiting the efficacy of available treatments. Here we investigate METH-induced changes to neuronal nitric oxide synthase (nNOS), parvalbumin and calretinin-expressing GABAergic interneuron populations within the nucleus accumbens (NAc), prefrontal cortex (PFC) and orbitofrontal cortex (OFC). We hypothesise that dysfunction or loss of these GABAergic interneuron populations may disrupt the excitatory/inhibitory balance within the brain. Male Long Evans rats ( N = 32) were trained to lever press for intravenous METH or received yoked saline infusions. Following 14 days of behavioural extinction, animals were given a non-contingent injection of saline or METH (1 mg/kg, IP) to examine drug-primed reinstatement to METH-seeking behaviours. Ninety minutes post-IP injection, animals were culled and brain sections were analysed for Fos, nNOS, parvalbumin and calretinin immunoreactivity in eight distinct subregions of the NAc, PFC and OFC. METH exposure differentially affected GABAergic populations, with METH self-administration increasing nNOS immunoreactivity at distinct locations in the prelimbic cortex and decreasing parvalbumin immunoreactivity in the NAc. METH self-administration triggered reduced calretinin immunoreactivity, whilst acute METH administration produced a significant increase in calretinin immunoreactivity. As expected, non-contingent METH-priming treatment increased Fos immunoreactivity in subregions of the NAc and PFC. Here we report that METH exposure in this model may alter the function of GABAergic interneurons in more subtle ways, such as alterations in neuronal firing or synaptic connectivity.
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.
Publisher: American Psychological Association (APA)
Date: 08-2017
DOI: 10.1037/BNE0000204
Abstract: Caffeine is a psychostimulant frequently consumed by adults and children, often in combination with high levels of sugar. Chronic pretreatment with either substance can lify both hetamine and cocaine-induced hyperactivity in rodents. The present study sought to elucidate whether age at the time of exposure to sugar and/or caffeine alters sensitivity to an acute illicit psychostimulant (meth hetamine, [METH]) challenge in adulthood. Adult and adolescent (Postnatal Day 35 on first day of treatment) male Sprague-Dawley rats were treated for 26 days with water, caffeine (0.6 g/L), 10% sucrose or their combination. Locomotor behavior was measured on the first and last day of treatment. Following 9-days treatment free, animals were challenged with saline (1 ml/kg, i.p.) or METH (1 mg/kg, i.p.) and locomotor activity was measured. During the treatment period, adolescent rats maintained a higher caffeine (mg/kg) dose than their adult counterparts. Adding sugar to caffeine increased adolescent consumption and the highest caffeine dose consumed was measured in these animals. Drinking sugar-sweetened caffeinated water or combination did not produce cross-sensitization to METH administration in either age group. Nevertheless, the finding that regular exposure through adolescence to caffeinated sugar-sweetened beverages could increase consumption of caffeine and sugar later in life is important, as there is a large body of evidence that has linked excess consumption of sugar-sweetened beverages to a broad range of other negative physical and mental health outcomes. (PsycINFO Database Record
Publisher: Elsevier BV
Date: 08-1999
DOI: 10.1016/S0306-4522(99)00214-6
Abstract: This study investigated the effect of ionotropic glutamate receptor agonist or antagonist administration into the nucleus accumbens on the maintenance of cocaine self-administration and the reinstatement of cocaine-seeking behavior. The stimulation of alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid or N-methyl-D-aspartate glutamate receptors in the nucleus accumbens with either alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid or 1-aminocyclobutane-cis-1,3-dicarboxylic acid, respectively, decreased the number of cocaine-reinforced responses, suggesting an enhancement in the rewarding properties of cocaine. In contrast, blockade of alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptors with N-methyl-D-aspartate, or N-methyl-D-aspartate receptors with dizocilpine maleate or 2-amino-5-phosphonovaleric acid had no selective effect on the maintenance of cocaine self-administration. Following one week of extinction from the reinforcing cue of the drug-paired lever, both alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid and 1-aminocyclobutane-cis-1,3-dicarboxylic acid treatment in the nucleus accumbens reinstated cocaine-seeking behavior. However, alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid treatment increased responding only on the drug-paired lever, while 1-aminocyclobutane-cis-1,3-dicarboxylic acid increased responding on both the drug-paired and non-drug-paired levers. These results suggest that stimulation of glutamate receptors in the nucleus accumbens augments the reinforcing effect of cocaine, yet glutamate transmission is not required to maintain cocaine self-administration. In addition, increased glutamate transmission in the nucleus accumbens may be involved in facilitating the relapse to cocaine-seeking behavior.
Publisher: Wiley
Date: 29-10-2013
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.
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.PBB.2019.06.002
Abstract: Addiction to the psychostimulant Meth hetamine (METH) is characterised by high rates of relapse. Currently there are no approved effective pharmacotherapies for METH dependence. The neuropeptide oxytocin (OXY) potently reduces METH-seeking behaviours in rodent models of relapse and is now being used in clinical trials to treat drug-dependent in iduals. However, OXY administration in humans may be impeded by its poor penetration of the brain. Therefore, identification of the neural mechanisms by which OXY reduces METH relapse may guide the development of improved OXY-based therapies for METH addiction. Systemic OXY administration is associated with attenuated METH-induced activity in the prelimbic cortex (PrL) a key brain region which exerts control over much of the reward and addiction circuitry. However, it is not known whether OXY acts directly in the PrL to cause reductions in drug-seeking and downstream brain activity. Therefore, the present study sought to determine whether OXY infused into the PrL reduces cue-induced and METH-primed reinstatement and METH-induced neuronal activity in the downstream nucleus accumbens core (NAcc). Male Sprague Dawley rats underwent intravenous METH self-administration, extinction, and subsequent reinstatement tests. OXY was infused bilaterally into the PrL prior to cue-induced (0, 1 μg/side) and METH-primed reinstatement (0, 0.33, 1.0, 3.0 μg/side). Finally, we quantified cFos immunofluorescence in the NAcc as a proxy for downstream neuronal activity following a PrL infusion of OXY (0, 1 μg/side) prior to METH-primed reinstatement. OXY in the PrL significantly reduced both cue-induced and METH-primed reinstatement. Additionally, intra-PrL OXY reduced METH-induced cFos expression in the rostral but not caudal pole of the NAcc. These findings demonstrate OXY action in the PrL in reducing METH-seeking behaviours and METH-induced activity in the reward circuit. Furthermore, these results suggest that the therapeutic effects of systemically administered OXY on reducing METH-seeking behaviours may involve the PrL-NAc pathway.
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.
Publisher: Elsevier BV
Date: 03-2020
DOI: 10.1016/J.NEUBIOREV.2018.08.014
Abstract: Early life trauma is strongly associated with an increased vulnerability to abuse illicit drugs and the impairment of neural development. This includes alterations to the development of the oxytocin system, which plays a pivotal role in the regulation of social behaviours and emotion. Dysregulation of this important system also contributes to increased susceptibility to develop drug addiction. In this review, we provide an overview of the animal models of early life stress that are widely used, and discuss the impact that early life stress has on drug-taking behaviour in adolescence and adulthood in both sexes. We link this to the changes that early life stress has on the endogenous oxytocin system, and how exogenously administered oxytocin may help to re-establish functioning of the system, and in turn, reduce drug-taking behaviour.
Publisher: Informa UK Limited
Date: 07-04-2017
DOI: 10.1080/13543784.2017.1313229
Abstract: Meth hetamine use is a serious public health concern in many countries and is second to cannabis as the most widely abused illicit drug in the world. Effective management for meth hetamine dependence remains elusive and the large majority of meth hetamine users relapse following treatment. Areas covered: Progression in the understanding of the pharmacological basis of meth hetamine use has provided us with innovative opportunities to develop agents to treat dependence. The current review summarizes relevant literature on the neurobiological and clinical correlates associated with meth hetamine use. We then outline agents that have been explored for potential treatments in preclinical studies, human laboratory phase I and phase II trials over the last ten years. Expert opinion: No agent has demonstrated a broad and strong effect in achieving MA abstinence in Phase II trials. Agents with novel therapeutic targets appear promising. Advancement in MA treatment, including translation into practice, faces several clinical challenges.
Publisher: Springer Science and Business Media LLC
Date: 26-03-2022
DOI: 10.1007/S00213-022-06103-X
Abstract: Stress exposure during adolescence contributes to developing a meth hetamine (METH) use disorder. However, most of the studies investigating addiction-related behaviours include only male rodents, despite METH addiction rates being higher in females. Furthermore, animal studies investigating the effects of stress on meth hetamine addiction have used only basic self-administration models which may not be sensitive to the effects of stress. This project explored whether adolescent isolation stress exposure increases the incidence of four key addiction-related behaviours in female rats. Thirty-two female rat pups were caged in groups of four or in idually during adolescence from postnatal (PND) day 22, with the latter being re-socialised in groups of four on PND 43. In adulthood, rats were tested for addiction-like behaviours in a METH self-administration paradigm modelling motivation to take METH, persistence in drug-seeking behaviour when METH was not available, resistance to extinction, and propensity to reinstate after a period of withdrawal. Adolescent social isolation resulted in lower METH intake during acquisition however, the paradigm modelling drug-seeking when the drug was unavailable engendered intermittent METH bingeing in all rats, abolishing the group differences in intake during this phase. Adolescent social isolation also accelerated extinction of non-reinforced lever pressing, and increased stress-primed reinstatement, compared to the group-housed rats. Adolescent social isolation stress alters various meth hetamine addiction-like behaviours in female rats.
Publisher: Elsevier BV
Date: 06-2022
Publisher: Frontiers Media SA
Date: 2010
Publisher: Elsevier BV
Date: 29-11-2001
DOI: 10.1016/S0166-4328(01)00239-X
Abstract: The aim of the present study was to investigate the capacity of repeated administration of cocaine (5 nmol/side) or the selective dopamine re-uptake inhibitor GBR 12909 (15 nmol/side) into the ventral tegmental area (VTA) to initiate behavioral sensitization to systemically administered cocaine (15 mg/kg, intraperitoneally). Following 1 week of withdrawal from intra-VTA treatment, cocaine or GBR 12909 pretreated animals displayed sensitized locomotor and rearing behavior to acute systemic cocaine administration. These data support the possibility that increased dopamine transmission in the VTA is involved in the cellular events that determine the initiation of behavioral sensitization to cocaine.
Publisher: SAGE Publications
Date: 05-06-2013
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.
Publisher: Elsevier BV
Date: 06-2013
Publisher: Frontiers Media SA
Date: 10-10-2018
Publisher: Springer Science and Business Media LLC
Date: 14-07-2020
Publisher: SAGE Publications
Date: 1998
DOI: 10.1177/026988119801200107
Abstract: Sensitization to cocaine refers to the behavioral model of cocaine addiction where the motor stimulant effect of cocaine is augmented for months after discontinuing a regimen of repeated cocaine injections. There has been speculation that the neuroadaptations mediating this sensitization phenomenon may, in part, underlie the behavioral changes produced by chronic cocaine abuse, including paranoia, craving and relapse. Criteria are proposed that may assist in determining which neuroadaptations are most relevant in this regard. Using these criteria, a model is presented that endeavors to incorporate neuroadaptations issuing directly from the pharmacological effects of cocaine and those arising from learned associations the organism makes with the cocaine injection procedure and pharmacological actions. It is proposed that the pharmacological neuroadaptations predominate in the manifestation of cocaine-induced paranoia, while the changes derived from learning may provide more critical underpinnings for cocaine craving and relapse.
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.NEUROPHARM.2016.08.038
Abstract: Psychotic disorders, such as schizophrenia, are characterized by prevalent and persistent executive deficits that are believed to be the result of dysfunctional inhibitory gamma-aminobutyric acid (GABA) processing of the prefrontal cortex (PFC). Meth hetamine (METH) is a commonly used psychostimulant that can induce psychotic and cognitive symptoms that are indistinguishable to schizophrenia, suggesting that METH-induced psychosis may have a similar GABAergic profile of the PFC. As the PFC consists of multiple subregions, the aim of the current study was to investigate changes to GABAergic mRNA expression in the prelimbic (PRL) and orbitofrontal (OFC) cortices of the PFC in rats sensitized to repeated METH administration. Male Sprague Dawley rats underwent daily METH or saline injections for 7 days. Following 14 days of withdrawal, rats were challenged with acute METH administration, RNA was isolated from the PRL and OFC and quantitative PCR was used to compare the relative expression of GABA enzymes, transporters, metabolites and receptor subunits. GAD
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.
Publisher: Elsevier BV
Date: 08-2021
DOI: 10.1016/J.PNPBP.2021.110279
Abstract: Early life stress (ELS) exposure alters brain development, increasing vulnerability for mental illness in adulthood, including depression. Despite this association, there are no approved pharmacotherapies to protect against the emergence of mental illness resulting from ELS. Recent preclinical work showed that oxytocin (OT) administration in adulthood reduced depressive-like behaviour in male rats with a history of ELS. However, the ability of an OT treatment regime in adolescence, a critical developmental window for the OT system, to prevent the expression of depressive-like behaviours following ELS has not been investigated. Therefore, the present study aimed to determine whether chronic OT administration can ameliorate the enduring effects of ELS on depressive-like behaviours in both male and female rats. Following birth, Long Evans rat pups (N = 107) underwent maternal separation (MS) for either 15 min (MS15) or 6 h (MS360) on postnatal days (PND) 1-21. During adolescence (PND 28-42), rats received a daily injection of either OT (1 mg/kg) or saline. During adulthood (PND 57 onwards), effort-related motivation was measured using a model of effortful choice (EC), while behavioural despair was measured using the forced swim test (FST). Lastly, body and organ weights were measured to examine the physiological impacts of ELS and chronic OT administration. Overall, in both sexes, MS360 increased behavioural despair yet had no impact on effort-related motivation. Importantly, adolescent OT administration prevented the MS360-induced increase in behavioural despair in both males and females. Additionally, MS360 resulted in persistent reductions in body weight in both sexes post-weaning and increased spleen weight in males and adrenal weight in females. OT treatment had no impact on body weight in either sex, but prevented the MS-induced increase in adrenal gland weight in females. Overall, these findings have important implications for using oxytocin as a preventative pharmacotherapy after ELS.
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.PNPBP.2017.03.018
Abstract: Schizophrenia is associated with significant pathophysiological changes to interneurons within the prefrontal cortex (PFC), with mRNA and protein changes associated with the GABA network localized to specific interneuron subtypes. Meth hetamine is a commonly abused psychostimulant that can induce chronic psychosis and symptoms that are similar to schizophrenia, suggesting that chronic METH induced psychosis may be associated with similar brain pathology to schizophrenia in the PFC. The aim of this study, therefore, was to examine mRNA expression of interneuron markers across two regions of the PFC (prelimbic (PRL) and orbitofrontal cortices (OFC)) following METH sensitization, an animal model of METH psychosis. We also studied the association between GABA mRNA expression and interneuronal mRNA expression to identify whether particular changes to the GABA network could be localized to a specific inhibitory cellular phenotype. METH sensitization increased the transcriptional expression of calbindin, calretinin, somatostatin, cholecyctokinin and vasoactive intestinal peptide in the PRL while parvalbumin, calbindin, cholectokinin and vasoactive intestinal peptide were upregulated in the OFC. Based on our previous findings, we also found significant correlations between GAD
Publisher: Elsevier BV
Date: 06-2015
DOI: 10.1016/J.NEUROSCIENCE.2015.03.028
Abstract: Meth hetamine (METH) is a psychostimulant that disrupts monoaminergic neurotransmission to evoke profound behavioral and physiological effects. Rapidly distributing to forebrain regions to increase synaptic concentrations of three monoamines (dopamine (DA), serotonin (5-HT) and noradrenaline (NA)), the medial prefrontal cortex (mPFC) is important in METH-altered behavioral and psychological profiles. Activation of the ventral mPFC can modify physiological variables, however, METH-evoked autonomic changes from this region are unknown. Therefore, the aim of this study was to characterize the respiratory, metabolic and cardiovascular effects of microinjection of METH, DA, 5-HT and NA into the ventral mPFC in urethane-anesthetized Sprague-Dawley rats. METH and NA microinjection evoked dose-related increases in heart rate, interscapular brown adipose tissue temperature and expired CO2, a pattern of response characteristic of non-shivering thermogenesis. NA and 5-HT microinjection elicited pressor and depressor responses, respectively, with matching baroreflex adjustments in sympathetic nerve activity while METH and DA evoked no change in vasomotor outflow. Low doses of METH and DA may evoke respiratory depression. These data suggest that METH's actions in the ventral mPFC, likely via adrenergic receptors, evoke non-shivering thermogenesis which may contribute to the increased body temperature and tachycardia seen in those that abuse METH.
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.
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.BBR.2015.10.026
Abstract: Inhibitory gamma-aminobutyric acid (GABA)-mediated neurotransmission plays an important role in the regulation of the prefrontal cortex (PFC), with increasing evidence suggesting that dysfunctional GABAergic processing of the PFC may underlie certain deficits reported across psychotic disorders. Meth hetamine (METH) is a psychostimulant that induces chronic psychosis in a subset of users, with repeat administration producing a progressively increased vulnerability to psychotic relapse following subsequent drug administration (sensitization). The aim here was to investigate changes to GABAergic mRNA expression in the PFC of rats sensitized to METH using quantitative polymerase chain reaction (qPCR). Male Sprague-Dawley rats (n=12) underwent repeated meth hetamine (intraperitoneal (i.p.) or saline injections for 7 days. Following 14 days of withdrawal, rats were challenged with acute meth hetamine (1mg/kg i.p.) and RNA was isolated from the PFC to compare the relative mRNA expression of a range of GABA enzymes, transporters and receptors subunits. METH challenge resulted in a significant sensitized behavioral (locomotor) response in METH pre-treated animals compared with saline pre-treated controls. The mRNAs of transporters (GAT1 and GAT3), ionotropic GABAA receptor subunits (α3 and β1), together with the metabotropic GABAB1 receptor, were upregulated in the PFC of sensitized rats compared with saline controls. These findings indicate that GABAergic mRNA expression is significantly altered at the pre and postsynaptic level following sensitization to METH, with sensitization resulting in the transcriptional upregulation of several inhibitory genes. These changes likely have significant consequences on GABA-mediated neurotransmission in the PFC and may underlie certain symptoms conserved across psychotic disorders, such as executive dysfunction.
Publisher: Elsevier BV
Date: 12-1996
DOI: 10.1016/S0304-3940(96)13222-5
Abstract: This study has investigated the effect of stimulating the region of origin of the mesolimbic dopaminergic system, the ventral tegmental area (VTA), with the substance P analogue DiMe-C7 on the regional expression of c-fos in the rat forebrain. We have previously shown this treatment produced a prolonged increase in blood pressure and heart rate which was mediated by both dopaminergic mechanisms and vasopressin release. Stimulation of the VTA resulted in increased levels of c-Fos immunostaining in several target regions of the mesolimbic dopaminergic system (such as the frontal cortex, olfactory tubercle, islands of Calleja and amygdala), with the notable exception of the nucleus accumbens. A marked increase in c-fos expression was also found in the supraoptic nucleus but not the paraventricular nucleus in the hypothalamus. These results support a role for a number of target areas of the mesolimbic dopaminergic system and vasopressin release in the increase in blood pressure and heart rate produced by stimulation of the VTA.
Publisher: Elsevier BV
Date: 08-1994
DOI: 10.1016/0304-3940(94)90068-X
Abstract: Central dopaminergic systems have been implicated in the regulation of blood pressure. We examined the effect on blood pressure of electrical or chemical stimulation of the rat brain ventral tegmental area (VTA) which is the region of origin of the A10 dopaminergic system. Electrical stimulation in urethane-anaesthetised rats (10-120 Hz, 80 microA) produced frequency-dependent increases in blood pressure (max 30-35 mmHg). These pressor responses could be significantly attenuated by pretreatment with the dopamine D2 receptor antagonist haloperidol, but not the D1 receptor antagonist SCH 23390. Chemical stimulation of the VTA, by microinjection of 10 nmol of the substance P analogue DiMe-C7, produced a sustained increase in blood pressure (max 10-15 mmHg), which could be completely prevented by pretreatment with haloperidol. These results suggest that stimulation of dopaminergic neurons in the VTA induces pressor responses and that projections from midbrain dopaminergic neurons, acting on dopamine D2 receptors, play a role in the regulation of blood pressure.
Publisher: MDPI AG
Date: 12-09-2012
Publisher: American Chemical Society (ACS)
Date: 17-10-2014
DOI: 10.1021/PR500719F
Abstract: Repeat administration of psychostimulants, such as meth hetamine, produces a progressive increase in locomotor activity (behavioral sensitization) in rodents that is believed to represent the underlying neurochemical changes driving psychoses. Alterations to the prefrontal cortex (PFC) are suggested to mediate the etiology and maintenance of these behavioral changes. As such, the aim of the current study was to investigate changes to protein expression in the PFC in male rats sensitized to meth hetamine using quantitative label-free shotgun proteomics. A meth hetamine challenge resulted in a significant sensitized locomotor response in meth hetamine pretreated animals compared to saline controls. Proteomic analysis revealed 96 proteins that were differentially expressed in the PFC of meth hetamine treated rats, with 20% of these being previously implicated in the neurobiology of schizophrenia in the PFC. We identified multiple biological functions in the PFC that appear to be commonly altered across meth hetamine-induced sensitization and schizophrenia, and these include synaptic regulation, protein phosphatase signaling, mitochondrial function, and alterations to the inhibitory GABAergic network. These changes could inform how alterations to the PFC could underlie the cognitive and behavioral dysfunction commonly seen across psychoses and places such biological changes as potential mediators in the maintenance of psychosis vulnerability.
Publisher: SLACK, Inc.
Date: 10-1998
Publisher: Springer Science and Business Media LLC
Date: 25-05-2020
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.PNPBP.2019.109681
Abstract: Behavioral sensitization to repeated psychostimulant administration has been proposed to reflect many of the neurochemical and behavioral changes that are characteristic of a range of disorders, including drug addiction and psychoses. While previous studies have examined the role of dopamine and glutamate neurotransmission in mediating sensitization, particularly within the prefrontal cortex (PFC), the role of inhibitory GABAergic processing of the PFC in the expression of sensitization is not well understood. Recent research, however, has proposed an emerging role of GABA synthesis, reuptake, ionotropic and metabotropic receptor regulation, and interneuronal changes following sensitization to meth hetamine and/or hetamine within the PFC. The aim of this review, therefore, is to synthesize research findings on changes to the GABAergic network following sensitization induced by hetamines (i.e., hetamine and/or meth hetamine) in the PFC. In addition to providing an overview of global PFC changes, we also provide evidence of regional specific inhibitory influences on sensitized circuitry, focusing on the prelimbic and orbitofrontal cortices. We propose a neural circuit through which inhibitory PFC GABA changes mediate sensitized disease states, focusing on the interaction between the prelimbic and orbitofrontal cortices with subcortical brain structures and the mesolimbic system. Methodological considerations and avenues for future research are also discussed.
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.
Publisher: Elsevier BV
Date: 10-2013
Publisher: Wiley
Date: 14-10-2016
Abstract: Caffeine is a psychostimulant commonly consumed with high levels of sugar. The increased availability of highly caffeinated, high sugar energy drinks could put some consumers at risk of being exposed to high doses of caffeine and sugar. Notably, research that has examined the consequences of this combination is limited. Here, we explored the effect of chronic exposure to caffeine and/or sugar on behavior and protein levels in the orbitofrontal cortex (OFC) of rats. The OFC brain region has been implicated in neuropsychiatric conditions, including obesity and addiction behaviors. Adult male Sprague-Dawley rats were treated for 26 days with control, caffeine (0.6 g/L), 10% sugar, or combination of both. Locomotor behavior was measured on the first and last day of treatment, then 1 week after treatment. Two hours following final behavioral testing, brains were rapidly removed and prepared for proteomic analysis of the OFC. Label-free quantitative shotgun analysis revealed that 21, 12, and 23% of proteins identified in the OFC were differentially expressed by sugar and/or caffeine. The results demonstrate that the intake of high levels of sugar and/or low to moderate levels of caffeine has different behavioral consequences. Moreover, each treatment results in a unique proteomic profile with different implications for neural health.
Publisher: Public Library of Science (PLoS)
Date: 16-04-2015
Publisher: Elsevier BV
Date: 08-1997
DOI: 10.1016/S0306-4522(97)00157-7
Abstract: The aim of the present study was to further characterize the involvement of the mesolimbic dopamine system in central blood pressure regulation, with particular emphasis on the interaction of this system with the effects of circulating vasopressin. In conscious rats we stimulated the release of endogenous dopamine from mesolimbic/mesocortical terminals by administration of the substance P analogue DiMe-C7 ([pGlu5, MePhe8, Sar9]-Substance P5-11 10 nmol) into the ventral tegmental area. Chemical stimulation of the ventral tegmental area resulted in a significant increase in blood pressure and heart rate. These effects were prevented by either bilateral electrolytic lesions of the hypothalamic supraoptic nucleus or by systemic pretreatment with the dopamine D2 receptor antagonist raclopride (0.5 mg/kg). Stimulation of the ventral tegmental area also produced a marked increase in the expression of the proto-oncogene c-fos in the supraoptic nucleus and a significant increase in plasma vasopressin levels, suggesting activation of vasopressinergic neurons in this nucleus. However, this effect of stimulation of the ventral tegmental area was not significantly inhibited by pretreatment with raclopride. We suggest that the effects on blood pressure and heart rate of stimulation of the ventral midbrain by micro-injection of DiMe-C7 are the result of combined activation of both dopaminergic and non-dopaminergic cell bodies in this region. Stimulation of non-dopaminergic cells in the ventral midbrain may induce a moderate increase in plasma vasopressin levels by activation of the supraoptic nucleus. An additional stimulation of dopaminergic cells in the ventral midbrain allows the increase in circulating vasopressin levels to become manifest as a pressor response, possibly by inhibition of vasopressin-induced facilitation of baroreflex responses.
Publisher: Public Library of Science (PLoS)
Date: 31-05-2013
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.
Publisher: Springer Science and Business Media LLC
Date: 12-11-2019
Publisher: Public Library of Science (PLoS)
Date: 18-08-2015
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.
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.
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.
Publisher: SAGE Publications
Date: 27-09-2018
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.
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.
Publisher: Springer Science and Business Media LLC
Date: 18-04-2022
DOI: 10.1007/S00213-022-06119-3
Abstract: Cannabidiol (CBD) and cannabidiolic acid (CBDA) are non-psychoactive components of the cannabis plant. CBD has been well characterised to have anxiolytic and anticonvulsant activity, whereas the behavioural effects of CBDA are less clear. Preclinical and clinical data suggests that CBD has antipsychotic properties and reduces meth hetamine self-administration in rats. An animal model that is commonly used to mimic the neurochemical changes underlying psychosis and drug dependence is meth hetamine (METH) sensitisation, where repeated administration of the psychostimulant progressively increases the locomotor effects of METH. The aim of this study was to determine whether CBD or CBDA attenuate METH-induced sensitisation of locomotor hyperactivity in rats. Eighty-six male Sprague Dawley rats underwent METH sensitisation protocol where they were subjected to daily METH (1 mg/kg on days 2 and 8, 5 mg/kg on days 3–7 i.p.) injections for 7 days. After 21 days of withdrawal, rats were given a prior injection of CBD (0, 40 and 80 mg/kg i.p.) or CBDA (0, 0.1, 10 and 1000 µg/kg i.p.) and challenged with acute METH (1 mg/kg i.p.). Locomotor activity was then measured for 60 min. Rats displayed robust METH sensitisation as evidenced by increased locomotor activity to METH challenge in METH-pretreated versus SAL-pretreated rats. CBD (40 and 80 mg/kg) reduced METH-induced sensitisation. There was no effect of any CBDA doses on METH sensitisation or acute METH-induced hyperactivity. These results demonstrate that CBD, but not CBDA, reduces METH sensitisation of locomotor activity in rats at pharmacologically effective doses, thus reinforcing evidence that CBD has anti-addiction and antipsychotic properties.
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.
Publisher: Wiley
Date: 2006
DOI: 10.1002/BDD.497
Abstract: AHN 1-055, a benztropine (BZT) analog, binds with high affinity to the dopamine transporter (DAT), possesses behavioral, pharmacokinetic (PK) and brain microdialysate dopamine (DA) profiles distinct from cocaine. Accordingly, the objectives of this study were to evaluate the pharmacokinetics and dopamine release of AHN 1-055, in the presence of cocaine. Male Sprague Dawley rats ( approximately 300 g) were administered 5 mg/kg of AHN 1-055 and cocaine i.v. and blood and brain s les were collected over 36 h. In addition, dialysis probes were stereotaxically implanted into the nucleus accumbens and extracellular fluid (ECF) DA levels were measured. PK and PD models were used to describe the relationship between the AHN 1-055, cocaine and DA levels. No significant (p< 0.05) differences were found in the PK parameters of AHN 1-055 alone (V(dss) = 18.7 l/kg, Cl = 1.8 l/h/kg and t(1/2) = 7.69 h) or AHN 1-055 with cocaine (V(dss)=17.4 l/kg, Cl = 1.9 l/h/kg and t(1/2) = 6.82 h). The brain-to-plasma (B/P) ratios (B/P(AHN 1-055) = 4.8 vs B/P(with cocaine) = 4.4) and half-lives (t(1/2(AHN 1-055)) = 6.2 h vs t(1/2(cocaine) = )5.6 h for AHN 1-055 alone and with cocaine were comparable. AHN 1-055 DA profiles were significantly different after co-administration with cocaine. There were no differences in the IC(50) for AHN 1-055, with cocaine, however, the IC(50) for cocaine was significantly reduced with AHN 1-055. The PK parameters of AHN 1-055 were not changed, however, the effect on DA levels was affected when cocaine was administered with AHNDA profile is affected when dosed with cocaine. This latter effect is a desirable attribute in the development of a medication as a potential substitute therapeutic medication for the treatment of cocaine abuse.
Publisher: Wiley
Date: 18-09-2013
Abstract: The typical Western diet, rich in high saturated fat and refined sugar (HFS), has been shown to increase cognitive decline with aging and Alzheimer's disease, and to affect cognitive functions that are dependent on the hippoc us, including memory processes and reversal learning. To investigate neurophysiological changes underlying these impairments, we employed a proteomic approach to identify differentially expressed proteins in the rat dorsal and ventral hippoc us following maintenance on an HFS diet. Rats maintained on the HFS diet for 8 weeks were impaired on a novel object recognition task that assesses memory and on a Morris Water Maze task assessing reversal learning. Quantitative label-free shotgun proteomic analysis was conducted on biological triplicates for each group. For the dorsal hippoc us, 59 proteins were upregulated and 36 downregulated in the HFS group compared to controls. Pathway ana-lysis revealed changes to proteins involved in molecular transport and cellular and molecular signaling, and changes to signaling pathways including calcium signaling, citrate cycle, and oxidative phosphorylation. For the ventral hippoc us, 25 proteins were upregulated and 27 downregulated in HFS fed rats. Differentially expressed proteins were involved in cell-to-cell signaling and interaction, and cellular and molecular function. Changes to signaling pathways included protein ubiquitination, ubiquinone biosynthesis, oxidative phosphorylation, and mitochondrial dysfunction. This is the first shotgun proteomics study to examine protein changes in the hippoc us following long-term consumption of a HFS diet, identifying changes to a large number of proteins including those involved in synaptic plasticity and energy metabolism. All MS data have been deposited in the ProteomeXchange with identifier PXD000028.
Publisher: Springer Science and Business Media LLC
Date: 26-08-2011
DOI: 10.1007/S00213-010-1982-9
Abstract: 3,4-Methylenedioxymeth hetamine (MDMA) abuse is a substantial problem in young adults. Due to a high focus on body image in this population, two main factors that may encourage MDMA use are the appetite suppressant and locomotor stimulant effects of this drug. The nucleus accumbens (NAc) is a brain region associated with the regulation of motivated and locomotor behaviours, and recent evidence suggests that NAc 5-HT4 receptors are likely to be involved in the appetite suppressant effect of MDMA. It has not yet been shown whether 5-HT4 receptors of the NAc are involved in the locomotor stimulant effects of MDMA, which may also contribute to a reduction in food intake. This study aimed to investigate the effect of local antagonism of serotonin 5-HT4 receptors in the NAc in the appetite suppressant and locomotor stimulant effects of MDMA. Male hooded Wistar rats underwent surgery for the implantation of bilateral NAc microinjection cannulae under isofluorane anesthesia. Following 5-7 days of recovery, the rats received bilateral microinjections of the 5-HT4 antagonist RS39604 into the NAc immediately prior to either saline or MDMA administration. Food intake, water intake, body weight and locomotor activity were measured. RS39604 significantly increased food intake and increased weight loss in MDMA-treated but not saline-treated rats. Measures of MDMA-induced water intake or locomotor activity were not altered by antagonist administration. These results demonstrate that 5-HT4 receptors in the NAc specifically regulate the appetite suppressant effects of MDMA but not MDMA-induced water intake or locomotor activity.
Publisher: American Chemical Society (ACS)
Date: 11-04-2016
DOI: 10.1021/ACS.JPROTEOME.5B01043
Abstract: Caffeine is a plant-derived psychostimulant and a common additive found in a wide range of foods and pharmaceuticals. The orbitofrontal cortex (OFC) is rapidly activated by flavours, integrates gustatory and olfactory information, and plays a critical role in decision-making, with dysfunction contributing to psychopathologies and neurodegenerative conditions. This study investigated whether long-term consumption of caffeine causes changes to behavior and protein expression in the OFC. Male adult Sprague-Dawley rats (n = 8 per group) were treated for 26 days with either water or a 0.6 g/L caffeine solution. Locomotor behavior was measured on the first and last day of treatment, then again after 9 days treatment free following exposure to a mild stressor. When tested drug free, caffeine-treated animals were hyperactive compared to controls. Two hours following final behavioral testing, brains were rapidly removed and prepared for proteomic analysis of the OFC. Label free shotgun proteomics found 157 proteins differentially expressed in the caffeine-drinking rats compared to control. Major proteomic effects were seen for cell-to-cell communication, cytoskeletal regulation, and mitochondrial function. Similar changes have been observed in neurological disorders including Alzheimer's disease, Parkinson's disease, and schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 14-05-2014
DOI: 10.1038/NPP.2014.111
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.
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.
Publisher: Elsevier BV
Date: 10-2013
Publisher: Wiley
Date: 06-01-2016
DOI: 10.1113/JP271257
Publisher: SAGE Publications
Date: 20-10-2020
Abstract: The incentive sensitisation theory of addiction posits that drug-associated stimuli become imbued with incentive motivational properties, driving pathological drug seeking. However, pre-existing variability in the incentive salience to non-drug reward cues (‘sign trackers’ (STs) ‘goal trackers’ (GTs)) is also predictive of the desire for and relapse to cocaine and opioids. Here, we asked whether variation in propensity to attribute incentive salience to a food cue is predictive of reinstatement to the highly addictive psychostimulant meth hetamine (METH), and whether treatment with the promising anti-addiction therapy oxytocin differentially reduces METH behaviour between STs and GTs. Rats were trained to associate a Pavlovian cue with delivery of a sucrose pellet over 8 days. They then received jugular vein catheters for intravenous METH self-administration, followed by behavioural extinction, and cue-induced and METH-primed reinstatement to METH-seeking behaviours. Oxytocin was administered prior to self-administration and reinstatement tests. Despite the self-administration of similar amounts of METH, STs reinstated more to METH cues than did GTs, yet METH-priming reinstated STs and GTs similarly. Furthermore, oxytocin attenuated cue-induced reinstatement more so in STs than in GTs, and reduced METH-primed reinstatement to a greater extent in the top quartile of reinstaters, indicating that oxytocin treatment may be most effective for those at highest risk of addiction. This pre-existing bias towards reward cues presents a possible tool to screen for METH addiction susceptibility and may be useful for understanding the neurobiology of addiction and for pharmacotherapeutic discovery.
Publisher: Cold Spring Harbor Laboratory
Date: 11-06-2021
DOI: 10.1101/2021.06.10.447470
Abstract: The ability to discriminate competing, external stimuli, and initiate contextually appropriate behaviors, is a key brain function. Neurons in the deep superior colliculus (dSC) integrate multisensory inputs and activate descending projections to premotor pathways responsible for orienting and attention, behaviors which involve adjustments to respiratory and cardiovascular parameters. However, the neural pathways that subserve the physiological components of orienting are poorly understood. We report that orienting responses to optogenetic dSC stimulation are accompanied by short-latency autonomic, respiratory and electroencephalographic effects in awake rats, closely mimicking those evoked by naturalistic alerting stimuli. Physiological responses were not accompanied by detectable aversion or fear and persisted under urethane anesthesia, indicating independence from emotional stress. Moreover, autonomic responses were replicated by selective stimulation of dSC inputs to a subregion in the ventromedial medulla containing spinally-projecting premotor neurons. This putative disynaptic pathway from the dSC represents a likely substrate for autonomic components of orienting.
Publisher: Elsevier BV
Date: 12-1995
DOI: 10.1016/0006-8993(95)00967-X
Abstract: Treatment with dopamine receptor agonists has been shown to induce centrally mediated effects on cardiovascular regulation. We have investigated the effect on blood pressure and heart rate of stimulating the release of endogenous dopamine in the brain from the mesolimbic/mesocortical (A10) dopaminergic system of conscious Sprague-Dawley rats. Stimulation of the region of origin of the A10 dopaminergic system, the ventral tegmental area (VTA), with local micro-injection of the substance P analogue DiMe-C7, produced a dose-dependent increase in blood pressure and heart rate. The injection of 10 nmol of DiMe-C7 produced a maximum increase in blood pressure of 15-20 mmHg at 10 min following administration and a maximum tachycardia of 70-80 B/min. Intravenous pretreatment with the dopamine D-1 receptor antagonist SCH 23390 (0.1 mg/kg) or the dopamine D-2 receptor antagonist raclopride (0.5 mg/kg) markedly inhibited the pressor response and revealed a bradycardia. Furthermore, the pressor response and tachycardia were completely blocked by pretreatment with the vasopressin V-1 receptor antagonist, Pmp1,O-Me-Tyr2-[Arg8]vasopressin (10 micrograms/kg). Pretreatment with the ganglion blocker, pentolinium (10 mg/kg), had little effect on the blood pressure response, however it attenuated the tachycardia. Micro-injection of 10 nmol of DiMe-C7 into a region 2 mm dorsal to the VTA had little effect on blood pressure yet produced a marked bradycardia. The administration of DiMe-C7 into the region of origin of the nigrostriatal A9 dopaminergic system, the substantia nigra, produced a slight but significant increase in blood pressure with little effect on heart rate. Intracerebroventricular administration of DiMe-C7 also produced a pressor response with a more pronounced tachycardia. The blood pressure responses produced by intranigral or i.c.v. injection of DiMe-C7 were not inhibited by pretreating the rats with raclopride. These results suggest an involvement of the mesolimbic A10 dopaminergic system in the regulation of blood pressure and heart rate through the activation of dopamine D-1 and D-2 receptors and vasopressin release.
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.YHBEH.2013.12.014
Abstract: The orexins are hypothalamic neuropeptides most well known for their roles in regulating feeding and sleeping behaviors. Recent findings suggest that orexin-A may also modulate anxiety, although how and when the orexin system is involved remains unclear. To address this, we investigated the dose-dependent effects of the orexin-1 receptor antagonist SB-334867 in two rodent models of anxiety: the cat odor avoidance model and the elevated plus maze. In both models we tested the effects of SB-334867 when anxiety is novel (Trial 1) and familiar (Trial 2). In the first experiment, Wistar rats were treated with vehicle or SB-334867 (5, 10 or 20mg/kg, i.p.) prior to their first or second exposure to cat odor. During Trial 1, rats treated with 10mg/kg of SB-334867 approached the cat odor stimulus more than vehicle-treated rats. During Trial 2 the effects were more marked, with 10mg/kg of SB-334867 increasing approach times, increasing the number of times rats exited the hide box to engage in exploratory behavior, and decreasing overall hide times. In addition, the 20mg/kg dose decreased general activity during Trial 2. In the second experiment, the effects of SB-334867 (10 and 20mg/kg) were tested in the elevated plus maze. There were no significant differences produced by drug treatment during either Trial 1 or Trial 2. Results suggest that SB-334867 decreases anxiety induced by some, but not all, stressors.
Publisher: Elsevier BV
Date: 2009
DOI: 10.1016/J.JNEUMETH.2008.09.009
Abstract: Previous research using free-operant procedures have reported that the Spontaneously Hypertensive Rat (SHR) is more impulsive and inattentive than the Wistar-Kyoto (WKY) rat. Recently these behavioural differences have been suggested to be a consequence of differences in the overall activity of these strains. This study compared SHRs to WKYs on locomotor activity and delay sensitivity using a delayed reinforcement (DR) and extinction (EXT) task. SHRs maintained higher locomotor activity than WKYs, however no significant group differences were found on the total lever presses in the DR or EXT tasks. During the DR task, SHRs shifted to selecting the immediate small reinforcer significantly faster than WKYs as the delay increased. WKYs predominantly selected the lever previously associated with the delayed large reinforcer throughout the EXT task, while the SHRs showed no such preference. The significant group differences found on lever selection during the DR and EXT tasks suggests that SHRs are more sensitive to delays, therefore providing further support for the face validity of the SHR as an animal model of ADHD.
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.BBR.2014.10.028
Abstract: Increasing evidence suggests that the orexin system is involved in modulating anxiety, and we have recently shown that cat odor-induced anxiety in rats is attenuated by the orexin receptor antagonist SB-334867. In the current experiment, c-Fos expression was used to map changes in neuronal activation following SB-334867 administration in the cat odor anxiety model. Male Wistar rats were exposed to cat odor with or without SB-334867 pre-treatment (10 mg/kg, i.p.). A naïve control group not exposed to cat odor was also used. Following cat odor exposure, brains were processed for c-Fos expression. Vehicle-treated rats showed an increase in anxiety-like behaviors (increased hiding and decreased approach toward the cat odor), and increased c-Fos expression in the posteroventral medial amygdala (MePV), paraventricular hypothalamus (PVN) and dorsal premammillary nucleus (PMd). In rats pretreated with SB-334867, approach scores increased and c-Fos expression decreased in the PVN and PMd. These results provide both behavioral and neuroanatomical evidence for the attenuation of cat odor-induced anxiety in rats via the orexin system.
Publisher: Springer Science and Business Media LLC
Date: 12-11-2004
Publisher: Elsevier BV
Date: 02-2019
DOI: 10.1016/J.NEURON.2019.01.004
Abstract: Neuroethics is central to the Australian Brain Initiative's aim to sustain a thriving and responsible neurotechnology industry. Diverse and inclusive community and stakeholder engagement and a trans-disciplinary approach to neuroethics will be key to the success of the Australian Brain Initiative.
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.
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.
Publisher: Wiley
Date: 11-2011
Publisher: Elsevier BV
Date: 10-2007
Publisher: Wiley
Date: 02-2016
Abstract: In most Westernized societies, there has been an alarming increase in the consumption of sugar-sweetened drinks. For many adults these drinks represent a substantial proportion of their total daily caloric intake. Here we investigated whether extended exposure to sugar changes behavior and protein expression in the orbitofrontal cortex (OFC). Male adult Sprague-Dawley rats (n = 8 per group) were treated for 26 days with either water or a 10% sucrose solution. Locomotor behavior was measured on the first and last day of treatment, then 1 week after treatment. Following the 1-week period free from treatment, sucrose treated rats were significantly more active than the control. Two hours following final behavioral testing, brains were rapidly removed and prepared for proteomic analysis of the OFC. Label free quantitative shotgun proteomic analyses of three rats from each group found 290 proteins were differentially expressed in the sucrose treated group when compared to the control group. Major changes in the proteome were seen in proteins related to energy metabolism, mitochondrial function and the cellular response to stress. This research does not seek to suggest that sugar will cause specific neurological disorders, however similar changes in proteins have been seen in neurological disorders such as Alzheimer's disease, Parkinson's disease and schizophrenia.
Publisher: Wiley
Date: 06-2020
DOI: 10.1111/JNE.12861
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.
Publisher: SAGE Publications
Date: 22-08-2008
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.
Publisher: Wiley
Date: 12-2022
DOI: 10.1113/JP283789
Abstract: The ability to discriminate competing external stimuli and initiate contextually appropriate behaviours is a key brain function. Neurons in the deep superior colliculus (dSC) integrate multisensory inputs and activate descending projections to premotor pathways responsible for orienting, attention and defence, behaviours which involve adjustments to respiratory and cardiovascular parameters. However, the neural pathways that subserve the physiological components of orienting are poorly understood. We report that orienting responses to optogenetic dSC stimulation are accompanied by short‐latency autonomic, respiratory and electroencephalographic effects in awake rats, closely mimicking those evoked by naturalistic alerting stimuli. Physiological responses were not accompanied by detectable aversion or fear, and persisted under urethane anaesthesia, indicating independence from emotional stress. Anterograde and trans‐synaptic viral tracing identified a monosynaptic pathway that links the dSC to spinally projecting neurons in the medullary gigantocellular reticular nucleus (GiA), a key hub for the coordination of orienting and locomotor behaviours. In urethane‐anaesthetized animals, sympathoexcitatory and cardiovascular, but not respiratory, responses to dSC stimulation were replicated by optogenetic stimulation of the dSC–GiA terminals, suggesting a likely role for this pathway in mediating the autonomic components of dSC‐mediated responses. Similarly, extracellular recordings from putative GiA sympathetic premotor neurons confirmed short‐latency excitatory inputs from the dSC. This pathway represents a likely substrate for autonomic components of orienting responses that are mediated by dSC neurons and suggests a mechanism through which physiological and motor components of orienting behaviours may be integrated without the involvement of higher centres that mediate affective components of defensive responses. image Neurons in the deep superior colliculus (dSC) integrate multimodal sensory signals to elicit context‐dependent innate behaviours that are accompanied by stereotypical cardiovascular and respiratory activities. The pathways responsible for mediating the physiological components of colliculus‐mediated orienting behaviours are unknown. We show that optogenetic dSC stimulation evokes transient orienting, respiratory and autonomic effects in awake rats which persist under urethane anaesthesia. Anterograde tracing from the dSC identified projections to spinally projecting neurons in the medullary gigantocellular reticular nucleus (GiA). Stimulation of this pathway recapitulated autonomic effects evoked by stimulation of dSC neurons. Electrophysiological recordings from putative GiA sympathetic premotor neurons confirmed short latency excitatory input from dSC neurons. This disynaptic dSC–GiA–spinal sympathoexcitatory pathway may underlie autonomic adjustments to salient environmental cues independent of input from higher centres.
Publisher: SAGE Publications
Date: 07-11-2013
Abstract: Impulsivity is characteristic of several mental health disorders and is largely mediated by the prefrontal cortex subregions: the medial prefrontal cortex (mPFC) and the orbitofrontal cortex (OFC). Dopamine (DA) and norepinephrine (NE) are known to modulate activity of the prefrontal cortex, however their direct role in impulsive choice is not known. The aim of the present study was to investigate the effect of microinjecting DA or NE compounds in the mPFC or OFC on impulsive choice as measured by a delayed reinforcement (DR) task in male Wistar Kyoto rats. Following training in the DR task, rats were pretreated with DA D 1 and D 2 receptor antagonists (SCH23390 3 μg/side, raclopride 3 or 6 μg/side) or NE α 1 and α 2 receptor agonists (phenylephrine 0.1 or 0.3 μg/side, guanfacine 1 or 3 μg/side, respectively) into the mPFC or OFC and the effect on impulsive behavior was assessed. Pretreatment with raclopride into the mPFC or OFC significantly increased impulsive choice, however only pretreatment with SCH23390 into the mPFC, and not the OFC, significantly increased impulsive choice. Pretreatment with the NE receptor agonists had no effect on impulsive choice. This study suggests that DA receptors, but not NE receptors, differentially mediate impulsive choice in sub-regions of the prefrontal cortex.
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.
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.
Publisher: Springer Science and Business Media LLC
Date: 04-2005
DOI: 10.1007/S11095-005-2488-8
Abstract: The benztropine (BZT) analogues bind with high affinity to the dopamine transporter (DAT) and demonstrate a behavioral and pharmacokinetic profile unlike that of cocaine. The development of a predictive pharmacokinetic harmacodynamic (PK/PD) model to characterize the concentration-effect relationship between the BZT analogues and brain dopamine (DA) levels is an important step in the evaluation of these compounds as potential cocaine abuse pharmacotherapies. Hence, the objective of this study was to mathematically characterize the PD of BZT analogues and cocaine, using appropriate PK/PD models. Dialysis probes were stereotaxically implanted into the nucleus accumbens of Sprague-Dawley rats (275-300 g). Extracellular fluid (ECF) DA levels were measured after intravenous administration of the BZT analogues AHN-1055 and AHN-2005, as well as cocaine using high performance liquid chromatography-electrochemical detection (HPLC-ECD). PD models were used to describe the relationship between the BZT analogues or cocaine and brain microdialysate DA, and suitability was based on standard goodness-of-fit criteria. The BZT analogues produced a sustained increase in brain microdialysate DA levels in comparison to cocaine. The time of maximum concentration (T(max)) for brain microdialysate DA was 2 h for AHN-1055 and 1 h for AHN-2005 compared to a T(max) of 10 min for cocaine. The duration of brain microdialysate DA elevation was approximately 12-24 h for the BZTs in comparison to 1 h for cocaine. An indirect model with inhibition of loss of response and a sigmoid E(max) model best described the PK/PD for the BZT analogues and cocaine, respectively. The 50% of maximum inhibition (IC(50)) of the loss of DA was lower for AHN-2005 (226 +/- 27.5 ng/ml) compared to AHN-1055 (321 +/- 19.7 ng/ml). In addition, the EC(50) for cocaine was 215 +/- 11.2 ng/ml. The slow onset and long duration of BZT analogue-induced DA elevation may avoid the reinforcing effects and craving of cocaine. Further, the developed models will be useful in characterizing the PK/PD of other analogues and aid in the assessment of the therapeutic efficacy of the BZT analogues as substitute medications for cocaine abuse.
Publisher: Informa UK Limited
Date: 10-10-2001
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.
Publisher: Elsevier BV
Date: 10-2016
DOI: 10.1016/J.YFRNE.2016.08.001
Abstract: The role of oxytocin in attenuating the abuse of licit and illicit drugs, including the psychostimulant meth hetamine, has been examined with increased ferocity in recent years. This is largely driven by the potential application of oxytocin as a pharmacotherapy. However, the neural mechanisms by which oxytocin modulates meth hetamine abuse are not well understood. Recent research identified an important role for the accumbens core and subthalamic nucleus in this process, which likely involves an interaction with dopamine, glutamate, GABA, and vasopressin. In addition to providing an overview of meth hetamine, the endogenous oxytocin system, and the effects of exogenous oxytocin on drug abuse, we propose a neural circuit through which exogenous oxytocin modulates meth hetamine abuse, focusing on its interaction with neurochemicals within the accumbens core and subthalamic nucleus. A growing understanding of exogenous oxytocin effects at a neurochemical and neurobiological level will assist in its evaluation as a pharmacotherapy for drug addiction.
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.
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.
Publisher: Frontiers Media SA
Date: 08-12-2021
Abstract: Clinical studies provide fundamental knowledge of substance use behaviors (substance of abuse, patterns of use, relapse rates). The combination of neuroimaging approaches reveal correlation between substance use disorder (SUD) and changes in neural structure, function, and neurotransmission. Here, we review these advances, placing special emphasis on sex specific findings from structural neuroimaging studies of those dependent on alcohol, nicotine, cannabis, psychostimulants, or opioids. Recent clinical studies in SUD analyzing sex differences reveal neurobiological changes that are differentially impacted in common reward processing regions such as the striatum, hippoc us, amygdala, insula, and corpus collosum. We reflect on the contribution of sex hormones, period of drug use and abstinence, and the potential impact of these factors on the interpretation of the reported findings. With the overall recognition that SUD impacts the brains of females and males differentially, it is of fundamental importance that future research is designed with sex as a variable of study in this field. Improved understanding of neurobiological changes in males and females in SUD will advance knowledge underlying sex-specific susceptibility and the neurobiological impact in these disorders. Together these findings will inform future treatments that are tailor designed for improved efficacy in females and males with SUD.
Start Date: 2009
End Date: 07-2012
Amount: $220,000.00
Funder: Australian Research Council
View Funded ActivityStart Date: 10-2022
End Date: 09-2025
Amount: $434,301.00
Funder: Australian Research Council
View Funded Activity