ORCID Profile
0000-0002-2380-7902
Current Organisations
James Cook University
,
University of Alberta
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Mental Health | Aboriginal and Torres Strait Islander Education | Aboriginal and Torres Strait Islander Health | Specialist Studies in Education
Aboriginal and Torres Strait Islander Health - Determinants of Health | Aboriginal and Torres Strait Islander Education | Curriculum not elsewhere classified |
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.NEUROPHARM.2016.11.020
Abstract: Tramadol is a well-known and effective analgesic. Recently it was shown that tramadol is also effective in human premature ejaculation. The inhibitory effect of tramadol on the ejaculation latency is probably due to its mechanism of action as a μ-opioid receptor agonist and noradrenaline/serotonin (5-HT) reuptake inhibitor. In order to test this speculation, we tested several doses of tramadol in a rat model of male sexual behavior and investigated two types of drugs interfering with the μ-opioid and the 5-HT system. First the μ-opioid receptor agonist properties of tramadol were tested with naloxone, a μ-opioid receptor antagonist. Second, the effects of WAY100,635, a 5-HT
Publisher: Elsevier BV
Date: 1994
DOI: 10.1016/0306-4530(94)90062-0
Abstract: Oxytocin (OXT), a neurohypophyseal hormone, has a wide range of behavioral effects outside its classic peripheral endocrine functions. OXT involvement in adaptive central nervous system processes has been demonstrated as an inhibitory, amnestic action on learning and memory in different paradigms. Because adaptation and learning are likely to be involved in the neural events leading to drug tolerance and dependence, the question logically arose whether OXT is able to influence the development of tolerance of and dependence on abused drugs. In this review, we summarize our results on the effects of OXT on opiate (including morphine, heroin, and the endogenous opiates beta-endorphin and enkephalin) tolerance and dependence, heroin self-administration, psychostimulant-induced behavioral changes, and behavioral tolerance and sensitization. The sites and mechanisms of action and the possible physiological role of OXT are also discussed. In the first part of this review the effects of exogenously administered OXT on both the acute and chronic behavioral effects of opiates and psychostimulants have been summarized. OXT inhibited the development of tolerance to morphine, heroin, beta-endorphin, and enkephalin, OXT also inhibited the development of cross-tolerance between the predominantly mu-agonist heroin and the predominantly delta-agonist enkephalin in mice. Naloxone-precipitated morphine withdrawal syndrome was also attenuated by OXT. Heroin self-administration was decreased by OXT administration in heroin-tolerant rats. OXT inhibited cocaine-induced exploratory activity, locomotor hyperactivity, and stereotyped behavior in rats and in mice. Behavioral tolerance to cocaine was also attenuated by OXT. On the contrary, OXT stimulated the development of behavioral sensitization to cocaine. OXT did not alter the stereotyped behavior induced by hetamine. In the second series of experiments, the sites of action of OXT on drug-related behavior were investigated. Intracerebro-ventricular (ICV) and intracerebral (IC) administration of an OXT-receptor antagonist inhibited the effects of peripherally administered OXT on morphine tolerance, heroin self-administration, and cocaine-induced sniffing behavior. This suggests the central, intracerebral location of OXT target sites. Local IC microinjection of OXT in physiological doses into the posterior olfactory nucleus, tuberculum olfactorium, nucleus accumbens, central amygdaloid nucleus, and the hippoc us inhibited the development of tolerance to and dependence on morphine as well as cocaine-induced sniffing behavior and tolerance to cocaine. The physiological role of endogenous OXT in acute morphine tolerance has also been demonstrated, since OXT antiserum (ICV) and OXT-receptor antagonist (injected into the basal forebrain structures) potentiated the development of morphine tolerance. Finally, we investigated the possible mechanisms of action of OXT on drug related behavior. Both morphine tolerance and dependence, and cocaine administration, increased dopamine utilization in the mesencephalon and in the nucleus accumbens, respectively. OXT treatment decreased the alpha-methylparatyrosine-induced dopamine utilization in the mesencephalon and in the nucleus accumbens-septal complex. Chronic OXT treatment decreased the number of apparent binding sites of dopamine in the basal forebrain area. It also inhibited a cocaine-induced increase in dopamine utilization in the nucleus accumbens, but not in the striatum. In light of this information, it appears that OXT inhibits the development of opiate tolerance, dependence, and self-administration as well as the acute behavioral actions of and chronic tolerance to cocaine. This suggests the possible role of this neuropeptide in the regulation of drug abuse. Therefore, OXT may act as a neuromodulator on dopaminergic neurotransmission in limbic-basal forebrain structures to regulate adaptive CNS processes leading to drug addiction.
Publisher: Elsevier BV
Date: 03-1995
DOI: 10.1016/0006-8993(95)00043-P
Abstract: Anxiety is a key symptom of the cocaine withdrawal syndrome in human addicts, and it is considered to be one of the major factors in precipitating relapse to chronic cocaine abuse. Corticotropin-releasing factor (CRF) plays an important role in the pathophysiology of anxiety and depression, and it may also be involved in the acute behavioral and neuroendocrine actions of cocaine. The role of endogenous CRF in cocaine withdrawal-induced anxiety was investigated in the present study. Animals were subjected to chronic cocaine (20 mg/kg, intraperitoneally, once a day for 14 days) administration. Rats tested 30 min after the last cocaine injection did not show withdrawal anxiety on the elevated plus maze or any alterations in brain CRF levels. Withdrawal (48 h) from chronic cocaine administration produced an intense anxiety-like behavior characterized by decreased open arm exploration. Immunoreactive CRF (CRF-LI) levels were selectively altered in the hypothalamus, in the amygdala and in the basal forebrain structures at the time of the behavioral anxiety, reflecting an increased activity of brain CRF systems. Daily intracerebroventricular (i.c.v.) pretreatment with an immunoserum raised against CRF completely prevented the development of anxiety induced by cocaine withdrawal. These data suggest that extrahypothalamic-limbic CRF hypersecretion may be involved in the development of anxiety related to cocaine withdrawal and that the CRF system may be a useful target for new pharmacotherapies for cocaine withdrawal and relapse.
Publisher: Public Library of Science (PLoS)
Date: 22-09-2015
Publisher: Springer New York
Date: 11-12-2019
DOI: 10.1007/978-1-4939-8994-2_5
Abstract: The forced swim test assesses learned helplessness, which is a feature of depression-like behavior in rodents. This test has also been used in testing the efficacy of existing and novel antidepressant drugs. It is based on the natural tendency of rodents to escape from water. Rodents are placed in a cylinder filled with water and the presumption is that those with a depression-like phenotype give up swimming earlier than those that are not depressed. Furthermore, antidepressant drugs reverse this effect. This chapter describes the basic setup and conduction of the test, along with interpretation of the results. It should be emphasized that this test should be conducted as part of a series of behavioral assessments in order to increase the accuracy of the results.
Publisher: Springer New York
Date: 11-12-2019
DOI: 10.1007/978-1-4939-8994-2_6
Abstract: Obsessive-compulsive disorder (OCD) can occur in several psychiatric illnesses such as autism spectrum disorders (ASD) and it is more prevalent in children. This condition is characterized by repeated and apparently meaningless behaviors such as frequent hand washing, counting, tapping, and rocking. This can disrupt normal socialization and in some cases lead to self-harm. Therefore there is interest in developing more effective therapies for in iduals suffering from these conditions. This chapter describes how to conduct the mouse marble burying test as a sensitive measure of compulsive behaviors.
Publisher: Springer New York
Date: 11-12-2019
DOI: 10.1007/978-1-4939-8994-2_7
Abstract: This chapter presents a method for assessing general behavior, well-being, and sensorimotor gating. A detailed protocol is given for assessment of nest building performance in female mice using a strict scoring system. The test can be used for assessing moods and behaviors associated with psychiatric disorders such as depression and schizophrenia. It can also be useful for testing movement disorders such as Parkinson disease.
Publisher: Springer New York
Date: 11-12-2019
DOI: 10.1007/978-1-4939-8994-2_8
Abstract: Psychiatric disorders affect approximately one quarter of people worldwide at some point in their lifetime. This chapter provides a step-by-step guide to conduct behavioral tests in adult mice for investigations of social behavior, without the need for specific equipment. This test should allow the identification of key abnormalities in social interactions that can be followed up by targeted, more complex, behavioral analysis aimed at identification of new biomarkers and potential drug targets.
Publisher: Elsevier BV
Date: 04-1990
DOI: 10.1016/0028-3908(90)90095-9
Abstract: Cocaine is a widely used drug of abuse. One of the characteristic effects of this stimulant drug in the CNS of mice is the induction of motor hyperactivity. It was demonstrated that cocaine-induced motor hyperactivity could be blocked by pimozide, a dopamine receptor blocker, suggesting that dopamine was involved in cocaine-induced hyperactivity. Oxytocin, a neurohypophyseal neuropeptide, also partially antagonized cocaine-induced motor hyperactivity. Moreover, oxytocin antagonized the increased utilization of dopamine, elicited by cocaine in the nucleus accumbens. The data suggest that oxytocin may influence the behavioural effects of cocaine by affecting dopaminergic neurotransmission in some regions of the brain.
Publisher: American Chemical Society (ACS)
Date: 06-2012
DOI: 10.1021/PR300197D
Abstract: Administration of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (PCP) to rodents is widely used as preclinical model for schizophrenia. Most studies on this model employ methods investigating behavior and brain abnormalities. However, little is known about the corresponding peripheral effects. In this study, we analyzed changes in brain and serum molecular profiles, together with alterations in behavior after acute PCP treatment of rats. Furthermore, abnormalities in peripheral protein expression of first and recent onset antipsychotic free schizophrenia patients were assessed for comparison with the preclinical model. PCP treatment induced hyperlocomotion and stereotypic behavior, which have been related to positive symptoms of schizophrenia. Multiplex immunoassay profiling of serum revealed molecular abnormalities similar to those seen in first and recent onset, antipsychotic free schizophrenia patients. Also, increased insulin levels were detected after administration of a glucose tolerance test (GTT), consistent with previous studies showing changes in insulin signaling in patients with schizophrenia. Finally, schizophrenia-relevant alterations in brain molecules were found in the hippoc us and to a lesser extent in the frontal cortex using liquid-chromatography mass spectrometry and (1)H nuclear magnetic resonance spectroscopy. In conclusion, this study identified behavioral and molecular alterations in the acute PCP rat model, which are also observed in human schizophrenia. We propose that the corresponding changes in serum in both animals and patients may have utility as surrogate markers in this model to facilitate discovery and development of novel drugs for treatment of certain pathological features of schizophrenia.
Publisher: Springer New York
Date: 11-12-2019
DOI: 10.1007/978-1-4939-8994-2_9
Abstract: The open field test is used in studies of the neurobiological basis of anxiety and screening for novel drug targets and anxiolytic compounds. This test uses a camera to measure movement of the test animal in the peripheral and central zones of a 42 × 42 × 42 cm polyvinyl chloride box. This chapter describes a protocol for carrying out the open-field test for assessment of locomotion and anxiety-like behavior in mice.
Publisher: Springer New York
Date: 11-12-2019
DOI: 10.1007/978-1-4939-8994-2_4
Abstract: The elevated plus maze test is used to measure anxiety-like behavior in rodents. It can be used to gain insight into conditions such as posttraumatic stress disorder (PTSD) and other conditions marked by anxious behavior. It can also be used as a component in screening of novel compounds for anxiolytic properties. This model is based on aversion to open spaces, which is seen as the animal spending more time in the enclosed arms of the maze. This chapter describes the steps necessary for setting up and conducting the test, along with interpretation of the results.
Publisher: CSIRO Publishing
Date: 2019
DOI: 10.1071/RD18205
Abstract: Sperm banking and AI could benefit endangered African wild dog conservation. However, it is unclear whether their dominance hierarchy causes a decrease in reproductive and sperm quality parameters in subordinate males that typically do not breed. In this study, we investigated the effect of social rank on male reproductive parameters, including faecal androgen and glucocorticoid metabolite concentrations, prostate and testes volume, preputial gland size, semen collection success and sperm quality. S les were obtained from captive males (prebreeding season: n=12 from four packs breeding season: n=24 from seven packs) that were classified as alpha (dominant), beta or gamma (subordinates) based on the frequency of dominant versus submissive behaviours. In the prebreeding season, semen was successfully collected from all alpha but only half the subordinate males, with urine contamination (associated with lower rank) significantly reducing total and progressive motility, sperm motility index, normal sperm morphology and acrosome integrity. The breeding season was associated with a significant increase in faecal androgens, prostate and testis volume, as well as progressive motility and the total number of spermatozoa ejaculated. However, with the exception of prostate volume (mean±s.e.m: 12.5±4.5, 7.1±1.0 and 7.3±1.0cm3 in alpha, beta and gamma males respectively P=0.035), all other reproductive and sperm quality parameters did not differ between males of each social rank. In conclusion, reproductive suppression of subordinate males appears to be behaviourally mediated, because males of all social ranks produce semen of similar quality, making them suitable candidates for sperm banking, particularly during the breeding season when sperm quality improves.
Publisher: Springer Science and Business Media LLC
Date: 2011
Publisher: Elsevier
Date: 1987
DOI: 10.1016/S0079-6123(08)60200-9
Abstract: The conserved TREX-2 transcription-export complex integrates transcription and processing of many actively transcribed nascent mRNAs with the recruitment of export factors at nuclear pores and also contributes to transcriptional memory and genomic stability. We report the crystal structure of the Sac3-Thp1-Sem1 segment of Saccharomyces cerevisiae TREX-2 that interfaces with the gene expression machinery. Sac3-Thp1-Sem1 forms a previously uncharacterized PCI-domain complex characterized by the juxtaposition of Sac3 and Thp1 winged helix domains, forming a platform that mediates nucleic acid binding. Our structure-guided mutations support the idea that the Thp1-Sac3 interaction is an essential requirement for mRNA binding and for the coupling of transcription and processing to mRNP assembly and export. These results provide insight into how newly synthesized transcripts are efficiently transferred from TREX-2 to the principal mRNA export factor, and they reveal how Sem1 stabilizes PCI domain-containing proteins and promotes complex assembly.
Publisher: Oxford University Press (OUP)
Date: 23-06-2020
DOI: 10.1093/IJNP/PYAA036
Publisher: Wiley
Date: 30-06-2022
DOI: 10.1111/EIP.13182
Abstract: No biological treatment has been firmly established for the at‐risk stage of psychotic disorder. In this study we aim to test if subthreshold psychotic symptoms can be effectively treated with cannabidiol (CBD), a non‐psychoactive compound of the plant Cannabis sativa . The question has taken on increased importance in the wake of evidence questioning both the need and efficacy of specific pharmacological interventions in the ultra‐high risk (UHR) for psychosis group. Three‐arm randomized controlled trial of 405 patients (135 per arm) aged 12–25 years who meet UHR for psychosis criteria. The study includes a 6‐week lead‐in phase during which 10% of UHR in iduals are expected to experience symptom remission. Participants will receive CBD (per oral) at doses 600 or 1000 mg per day (fixed schedule) for 12 weeks. Participants in the third arm of the trial will receive matching placebo capsules. Primary outcome is severity of positive psychotic symptoms as measured by the Comprehensive Assessment of At‐Risk Mental States at 12 weeks. We hypothesize that CBD will be significantly more effective than placebo in improving positive psychotic symptoms in UHR patients. All participants will also be followed up 6 months post baseline to evaluate if treatment effects are sustained. This paper reports on the rationale and protocol of the Cannabidiol for At Risk for psychosis Youth (CanARY) study. This study will test CBD for the first time in the UHR phase of psychotic disorder.
Publisher: The Endocrine Society
Date: 1995
DOI: 10.1210/JCEM.80.1.7829639
Abstract: The ultradian release of ACTH and cortisol was investigated in six male rhesus monkeys (Macaca mulatta) with an intensive (2-min) blood-s ling procedure to investigate micropulsatile hormone secretory patterns. A sensitive and specific immunoradiometric assay was used to measure plasma ACTH concentrations. An objective pulse detection algorithm (Cluster) was used to assess the pulsatility of ACTH and cortisol release. The temporally coincident release of ACTH and cortisol was also examined. Venous blood s les were collected (over < 15 s) every 2 min for 120 min beginning at 1300 h. The number of ACTH peaks (3.2 peaks/h), interpulse intervals (19 +/- 2.4 min), and pulse litudes (9.7 +/- 1.6 pmol/L) in rhesus monkey were similar to corresponding measures of ACTH release in humans (3.3 peaks/h, 18 +/- 0.8 min, and 4.7 +/- 1.0 pmol/L, respectively). The number of cortisol peaks (2.3 peaks/h), interpulse interval (26 +/- 8.6 min), and other characteristics of pulsatile cortisol release were also determined. There was a 32.4% exact concordance of ACTH with cortisol peaks (11 of 34 P < 0.001). Fifty-six percent of ACTH peaks (19 of 34) were followed by a cortisol peak within 10 min (P < 0.02). There was a significant correlation between the ACTH and coincident cortisol pulse litudes (P < 0.0001). The litudes of ACTH peaks coincident with cortisol peaks at 0 min time lag were significantly higher than ACTH peaks not temporally coupled with cortisol peaks. Our data indicate that 1) high frequency, low litude micropulsatile ACTH secretion in rhesus monkeys is very similar to the high frequency ACTH rhythm in humans 2) temporally concordant ACTH and cortisol release episodes may be litude coupled and 3) an adequate incremental ACTH pulse litude may elicit a concurrent cortisol release episode from the adrenal cortex. These data suggest that the rhesus monkey is a potentially useful model for the study of neuroendocrine control of ACTH release.
Publisher: BMJ
Date: 2013
Publisher: No publisher found
Date: 1991
DOI: 10.1016/0143-4179(91)90073-R
Abstract: The effects of oxytocin (OXT), arginine- and lysine-vasopressin (AVP and LVP) and an OXT-receptor antagonist on cocaine-induced sniffing behaviour were investigated in rats. OXT, but not AVP or LVP injected subcutaneously (s.c.) attenuated cocaine-induced sniffing. The effect of OXT (s.c.) was inhibited by an OXT-receptor antagonist administered intracerebroventricularly (i.c.v.). I.c.v. administration of different doses of OXT in nanogram quantities caused a dose-dependent attenuation of cocaine-induced sniffing. Local cerebral microinjection of OXT into the accumbens nucleus and olfactory tubercle but not into the olfactory nucleus, central amygdaloid nucleus or caudate nucleus, inhibited the cocaine-induced sniffing behaviour. These results demonstrate that OXT selectively attenuates the cocaine-induced stereotyped behaviour through basal forebrain target sites.
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.NUTRES.2017.11.008
Abstract: Obesity and other lifestyle diseases in modern society can be related to historical dietary changes from diets balanced in omega-6 and omega-3 to the unbalanced "Western-type" diet. It is recognized that diet influences the murine and human gut microbiome, and most research indicates that microbial ersity and composition are altered by high-fat diets (HFDs). However, good knowledge about the effects of early exposure to HFD on the maturation and structure of the bacterial community is limited. Using mice as model, we hypothesized that an HFD alters the early dynamic of the gut bacterial community toward an unstable/unhealthy state. By sequencing the V3 and V4 regions of the 16S ribosomal ribonucleic acid gene, we investigated the bacterial community in fecal s les of mice fed a control diet and an HFD at weaning (s ling time 1) and after 8 weeks of dietary intervention (11weeks of age s ling time 2). Natural temporal microbiome maturation was evidenced by a general increase in microbial ersity and shifts in microbial community between s ling times 1 and 2 toward a mature community. However, the HFD led to significant structural segregation of the microbiome compared with controls the HFD diet repressed health-enhancing bacteria (eg, Bifidobacterium and Akkermansia) and promoted health-detracting bacteria (ie, those associated with gut disorders, eg, Dorea). We suggest that early-life consumption of HFD negatively impacts the natural gut bacterial community maturation leading toward a potentially persistent unhealthy stage.
Publisher: MDPI AG
Date: 06-04-2022
Abstract: The coronavirus (COVID-19) disease pandemic has been associated with adverse psychological outcomes. This cross-cultural study (N = 1326, 71% female) aimed to investigate Canadian and Australian adolescents’ subjective experiences of COVID-19, gender differences, and psychological implications. Mixed-methods analyses were used to examine differences in COVID-19 experiences and mental health outcomes between country and gender in a Canadian (N = 913, 78% female) and an Australian s le (N = 413, 57% female) of adolescents. Canadian adolescents reported increased COVID-19 discussions and more concerns related to their COVID-19 experiences compared to Australian adolescents. Girls consistently reported more concerns related to COVID-19 and poorer psychological outcomes compared to boys. School lockdown for the Canadian s le may have played a role in these country differences. Further, girls might be at significantly more risk for mental health concerns during COVID-19, which should be considered in adolescent mental health initiatives during the pandemic. Although school disruption and separation of peers due to the pandemic likely have a role in adolescent perceived stressors and mental health, the differences between Canadian and Australian adolescents were less clear and future investigations comparing more objective pre-COVID-19 data to current data are needed.
Publisher: Springer International Publishing
Date: 2019
DOI: 10.1007/978-3-030-25650-0_5
Abstract: This chapter reviews the efficacy of the ketogenic diet in a variety of neurodegenerative, neurodevelopmental and metabolic conditions throughout different stages of life. It describes conditions affecting children, metabolic disorders in adults and disorderrs affecting the elderly. We have focused on application of the ketogenic diet in clinical studies and in preclinical models and discuss the benefits and negative aspects of the diet. Finally, we highlight the need for further research in this area with a view of discovering novel mechanistic targets of the ketogenic diet, as a means of maximising the potential benefits/risks ratio.
Publisher: Frontiers Media SA
Date: 11-08-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2019
Publisher: Elsevier BV
Date: 05-1985
DOI: 10.1016/0028-3908(85)90026-7
Abstract: The effects of oxytocin (OXT) and of dipeptides derived from the C-terminal portion of oxytocin (Z-prolyl-leucine and Z-prolyl-D-leucine) on the development of acute and chronic tolerance to, and dependence on morphine were tested in the mouse. Oxytocin and the dipeptides attenuated the development of acute and chronic tolerance to the antinociceptive effect of morphine and delayed the onset of the naloxone-precipitated withdrawal syndrome. Both oxytocin and Z-prolyl-D-leucine affected drug-induced behavioural responses related to dopamine (DA) in the brain. Thus, oxytocin potentiated the hypermotility induced by a large dose of apomorphine and decreased the supersensitivity of the DA receptors. Small doses of Z-prolyl-D-leucine inhibited the hypomotility elicited by a small dose of apomorphine and potentiated the hyperactivity induced by hetamine. The data indicate that both oxytocin and Z-prolyl-D-leucine affect tolerance to and dependence on morphine. While oxytocin interacts mainly with postsynaptic DA-ergic neuronal elements, the dipeptide primarily affects DA-ergic neurotransmission at the presynaptic level.
Publisher: Elsevier BV
Date: 08-1989
Publisher: Elsevier BV
Date: 07-2020
Publisher: Elsevier BV
Date: 11-1995
DOI: 10.1016/0091-3057(95)00145-M
Abstract: The development of cross-tolerance to an analgesic effect was observed between two mu-receptor agonists, heroin and fentanyl. Repeated treatments with heroin twice a day for 4 days resulted in a decreased nociceptive effect to fentanyl on day 5. The fentanyl dose-response line shifted to the right, and was considered to be a sign of the development of cross-tolerance. Peripheral treatment with oxytocin did not block the development of heroin-fentanyl cross-tolerance. However, intracerebroventricular administration of oxytocin blocked the development of tolerance, causing a leftward shift in the dose-response curve and supporting the assumption that oxytocin blocks the development of heroin-fentanyl cross-tolerance via CNS mechanisms.
Publisher: No publisher found
Date: 1993
DOI: 10.1016/0091-3057(93)90106-4
Abstract: It has previously been demonstrated that cocaine stimulates the hypothalamic-pituitary-adrenal (HPA) axis through hypothalamic corticotropin-releasing factor (CRF) secretion. The role of different neurotransmitters in mediation of the cocaine-induced elevation of plasma corticosterone (CORT) were investigated in rats by using transmitter antagonists. Peripheral (IP) pretreatment with a dopaminergic antagonist, pimozide (0.01-1.0 mg/kg, IP), a noradrenergic blocker, phenoxybenzamine (1.0-4.0 mg/kg, IP), a beta-adrenergic blocker, propranolol (0.2-10 mg/kg, IP), an opiate antagonist, naloxone (1.0-4.0 mg/kg, IP), and a muscarinic cholinergic antagonist, atropine (1.0-4.0 mg/kg, IP), inhibited the cocaine-induced CORT response dose dependently. A similar dose-dependent inhibition of the plasma CORT response induced by cocaine was observed after the ICV route of administration of these antagonists in microgram quantities. None of the investigated IP or ICV doses of transmitter antagonists altered the basal CORT level. These results suggest that the activation of multiple neurotransmitter systems, including catecholaminergic, opiate, and cholinergic systems, might be responsible for the cocaine-induced HPA axis activation, probably through the specific receptors located in the CNS.
Publisher: Elsevier BV
Date: 02-1997
DOI: 10.1016/S0143-4179(97)90013-5
Abstract: Recent data from various laboratories suggest that the activation of endogenous corticotropin-releasing factor (CRF) may contribute to the behavioral and neuroendocrine effects of cocaine. In the present study, the time-dependent variations in CRF-like immunoreactivity (CRF-LI) in the hypothalamus and several extrahypothalamic brain regions were determined after acute cocaine administration to handled rats. The intraperitoneal injection of 7.5 mg/kg cocaine led to a significantly decreased CRF-LI level in the basal forebrain and to a significantly increased CRF-LI level in the amygdala 60 min after administration, while the CRF-LI content was decreased in the hypothalamus and in the hippoc us 180 min after cocaine treatment. These results suggest that the durations of the effects of cocaine on CRF-LI are in the brain region-specific, which might contribute to the mediation of the erse behavioral and neuroendocrine effects of cocaine.
Publisher: Canadian Science Publishing
Date: 08-2010
DOI: 10.1139/X10-095
Abstract: Detailed radial measurements of wood properties, taken at breast height, were obtained from control pollinated seedlings and a selection of 13 year old radiata pine ( Pinus radiata D. Don) clones. Using these data the key objectives of this study were to determine (i) the magnitude of mean clonal variation in modulus of elasticity (MOE) and properties affecting MOE (density and microfibril angle (MFA)) and (ii) whether there is a significant age × clone interaction for these traits. All wood properties were significantly affected by the main and interactive effects of age and clone. There was a relatively linear increase in both MOE and density with tree age, while MFA declined linearly with tree age. Values of density and MOE erged between the clonal extremes from age 3 to age 12. After erging markedly up to age 6, differences in MFA between clonal extremes remained relatively constant to age 12. At age 12, values for density, MFA, and MOE varied between clonal extremes by, respectively, 194 kg·m –3 (465–659 kg·m –3 ), 11.3° (9.6–20.9°), and 11.2 GPa (10.4–21.6 GPa). The seedling material had a relatively intermediate ranking, across the age range, for all traits considered.
Publisher: Elsevier
Date: 2011
Publisher: Elsevier BV
Date: 11-1988
DOI: 10.1016/0006-8993(88)90401-5
Abstract: It has previously been shown that endogenous oxytocin (OXT) inhibits the development of acute morphine tolerance. The role of OXT receptors in the central nervous system (CNS) was therefore studied by using a specific OXT receptor antagonist, N-acetyl-(2-O-methyltyrosin)-OXT (ACME-OXT). ACME-OXT (1 pg) was injected into the posterior olfactory nucleus, central amygdaloid nucleus, ventral hippoc us, caudate nucleus or lateral cerebral ventricle. The antagonist facilitated the development of tolerance to morphine when injected into the posterior olfactory nucleus, central amygdaloid nucleus or ventral hippoc al areas, which are known to contain OXT binding sites. When administered into the caudate nucleus (with no OXT binding sites) or the lateral cerebral ventricle, it had no effect on morphine tolerance. Our results suggest that the limbic forebrain OXT receptors play an important inhibitory role in adaptive responses to morphine.
Publisher: The Endocrine Society
Date: 09-1995
DOI: 10.1210/JCEM.80.9.7673418
Abstract: Cocaine stimulates ACTH secretion by a corticotropin-releasing factor (CRF)-dependent mechanism in male rats, rhesus monkeys, and humans. To determine the generality of this effect, we examined the effects of acute cocaine administration on the pulsatile release of ACTH and cortisol in three ovariectomized (OVX) rhesus monkeys and compared its effects to stimulation with CRF. Venous blood s les were collected at 2-min intervals for 60 min before and after iv administration of cocaine (0.4 and 0.8 mg/kg) and CRF (1.0 and 10 micrograms/kg). Cluster analysis procedures were used to evaluate the pulsatile characteristics of ACTH and cortisol release. After placebo administration, an ACTH pulse frequency of 3 peaks/h was detected. After cocaine administration, plasma cocaine levels peaked at 92 +/- 3.0 and 201 +/- 60 ng/mL within 2 min. However, in contrast to normal intact males, cocaine did not stimulate the pulsatile release of ACTH in OVX females. Cocaine (0.4 mg/kg) decreased ACTH incremental peak height and valley levels compared with pre-cocaine values, and a higher dose of cocaine produced no changes in ACTH release. Bolus injection of a low dose of CRF (1.0 micrograms/kg, iv) significantly increased ACTH incremental peak height (P < 0.05), and a higher dose of CRF (10 micrograms/kg) increased ACTH peak litude, percentage increase in peak litude, area under the peaks, and incremental peak heights as well as ACTH valley level and nadir (10 micrograms/kg, iv) (P < 0.05). ACTH pulse frequency did not change after CRF or cocaine administration. Pulsatile release of cortisol was 2.7 peaks/h under placebo conditions and did not change after cocaine or CRF administration. Cortisol pulse litude was increased after low and high doses of CRF. High doses of CRF (10 micrograms/kg) also increased the mean level of cortisol valleys. In summary, we found that CRF but not cocaine stimulated pulsatile ACTH and cortisol release in OVX rhesus monkeys. The profound ACTH response to CRF challenge suggests that the CRF sensitivity and the ACTH release capacity of the anterior pituitary corticotroph cells were intact. The lack of stimulatory effects of cocaine on the hypothalamic-pituitary-adrenal axis in OVX monkeys, in contrast to normal male monkeys, may reflect the absence of gonadal steroids.
Publisher: Wiley
Date: 05-02-1999
DOI: 10.1046/J.1432-1327.1999.00153.X
Abstract: The composition and properties of the tricarboxylic acid cycle of the microaerophilic human pathogen Helicobacter pylori were investigated in situ and in cell extracts using [1H]- and [13C]-NMR spectroscopy and spectrophotometry. NMR spectroscopy assays enabled highly specific measurements of some enzyme activities, previously not possible using spectrophotometry, in in situ studies with H. pylori, thus providing the first accurate picture of the complete tricarboxylic acid cycle of the bacterium. The presence, cellular location and kinetic parameters of citrate synthase, aconitase, isocitrate dehydrogenase, alpha-ketoglutarate oxidase, fumarate reductase, fumarase, malate dehydrogenase, and malate synthase activities in H. pylori are described. The absence of other enzyme activities of the cycle, including alpha-ketoglutarate dehydrogenase, succinyl-CoA synthetase, and succinate dehydrogenase also are shown. The H. pylori tricarboxylic acid cycle appears to be a noncyclic, branched pathway, characteristic of anaerobic metabolism, directed towards the production of succinate in the reductive dicarboxylic acid branch and alpha-ketoglutarate in the oxidative tricarboxylic acid branch. Both branches were metabolically linked by the presence of alpha-ketoglutarate oxidase activity. Under the growth conditions employed, H. pylori did not possess an operational glyoxylate bypass, owing to the absence of isocitrate lyase activity nor a gamma-aminobutyrate shunt, owing to the absence of both gamma-aminobutyrate transaminase and succinic semialdehyde dehydrogenase activities. The catalytic and regulatory properties of the H. pylori tricarboxylic acid cycle enzymes are discussed by comparing their amino acid sequences with those of other, more extensively studied enzymes.
Publisher: Springer New York
Date: 11-12-2019
DOI: 10.1007/978-1-4939-8994-2_10
Abstract: The Y-maze can be used to assess short term memory in mice. Spontaneous alternation, a measure of spatial working memory, can be assessed by allowing mice to explore all three arms of the maze and is driven by an innate curiosity of rodents to explore previously unvisited areas. A mouse with intact working memory, and hence intact prefrontal cortical functions, will remember the arms previously visited and show a tendency to enter a less recently visited arm. Spatial reference memory, which is underlined by the hippoc us, can also be tested by placing the test mice into the Y-maze with one arm closed off during training. After an inter-trial interval of for ex le 1 h, the mouse should remember which arm it has not explored previously and should visit this arm more often. This chapter describes the pre-test conditions, the materials required and the protocol for conducting and interpreting the results of these two related tests.
Publisher: Elsevier BV
Date: 04-2011
DOI: 10.1016/J.BBR.2010.12.029
Abstract: We examined juvenile social recognition and discrimination in mice with early post-natal onset, transgenic CRF over-expression (CRF-OE) and in their wild-type littermates (WT). CRF-OE mice showed enhanced social investigation during the first encounter, normal short-term and facilitated long-term social recognition memory, compared to WT. These results suggest that chronically elevated brain CRF tone may contribute in better remembering ethologically relevant and emotionally salient stimuli, such as social interaction.
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.NEUBIOREV.2022.104605
Abstract: Adverse Childhood Experiences (ACEs) are stressful and/or traumatic experiences associated with an increased lifetime risk of negative health outcomes. The Allostatic Load (AL) is a measure of multisystem dysregulation, resulted by chronic stress. We systematically reviewed the English language literature on the association between ACEs and AL to identify the clinical risk profile, with the exclusion of reviews and preclinical studies. Searches covered the publication period up to the 1
Publisher: Informa UK Limited
Date: 03-08-2018
Publisher: Elsevier BV
Date: 12-2015
Publisher: Elsevier BV
Date: 07-1986
DOI: 10.1016/0376-8716(86)90087-6
Abstract: Acute morphine tolerance was induced in mice by subcutaneous (s.c.) injection of a high dose (30 or 100 mg/kg) of morphine. The degree of tolerance was estimated 5 h later. Intracerebroventricular (i.c.v.) injection of graded doses of oxytocin (OXT) dose-dependently attenuated the development of tolerance. i.c.v. injection of a specific anti-OXT serum, on the other hand, facilitated the development of tolerance. Neither OXT nor anti-OXT serum had any effect on the pain sensitivity in morphine-naive mice nor did these treatments modify the antinociceptive action of a single morphine treatment. It is concluded that the endogenous OXT of the mouse brain is normally involved in the adaptive response of the organism, leading to the development of morphine tolerance.
Publisher: Elsevier BV
Date: 1994
DOI: 10.1016/0143-4179(94)90090-6
Abstract: As corticotropin-releasing factor (CRF) and oxytocin (OXT) are released in response to various stressors and a role of CRF in stress-induced OXT secretion has been proposed by previous authors, the present experiments were scheduled to investigate the participation of the brain CRF system in the stress-evoked release of OXT, arginine-8-vasopressin (AVP) and corticosterone. CRF-antiserum (AS) was given into the lateral ventricle of the brain of Wistar male rats, and 24 h later, the injection was repeated 30 min prior to ether stress followed by decapitation in 5 min. Plasma OXT and AVP were measured by radioimmunoassay and corticosterone by fluorimetry. Ether stress increased the levels of corticosterone and OXT, but not that of AVP. CRF-AS alone did not change the secretion of these hormones. CRF-AS pretreatment blocked the corticosterone-releasing action of ether stress, whereas it exerted no influence on the stress-induced OXT secretion into the circulation. There was no effect of a combined application of CRF-AS and stress on the plasma AVP level. These results suggest that the central CRF system is involved in the ether stress-elicited corticosterone response, however CRF is unlikely to be connected with the regulation of OXT secretion under these experimental conditions.
Publisher: Springer Science and Business Media LLC
Date: 24-11-2015
DOI: 10.1038/NG.3153
Abstract: Temple-Baraitser syndrome (TBS) is a multisystem developmental disorder characterized by intellectual disability, epilepsy, and hypoplasia or aplasia of the nails of the thumb and great toe. Here we report damaging de novo mutations in KCNH1 (encoding a protein called ether à go-go, EAG1 or KV10.1), a voltage-gated potassium channel that is predominantly expressed in the central nervous system (CNS), in six in iduals with TBS. Characterization of the mutant channels in both Xenopus laevis oocytes and human HEK293T cells showed a decreased threshold of activation and delayed deactivation, demonstrating that TBS-associated KCNH1 mutations lead to deleterious gain of function. Consistent with this result, we find that two mothers of children with TBS, who have epilepsy but are otherwise healthy, are low-level (10% and 27%) mosaic carriers of pathogenic KCNH1 mutations. Consistent with recent reports, this finding demonstrates that the etiology of many unresolved CNS disorders, including epilepsies, might be explained by pathogenic mosaic mutations.
Publisher: Springer Science and Business Media LLC
Date: 22-06-2001
Abstract: Prepulse inhibition (PPI) of the startle response in mice is increasingly used as a paradigm of sensory gating with potential predictive and construct validity towards schizophrenia. Establishment of a mouse PPI paradigm in which typical and atypical antipsychotic drugs directly improve a low performance PPI. Three strains of mice--C57Bl/6J, 129S6/SvEvTac and DBA/2J--were tested in a startle paradigm with three prepulse intensities, 2, 4 and 8 dB above background. Under these conditions, risperidone (0, 0.25, 0.5 and 1 mg/kg i.p.) and clozapine (0, 1, 3 and 9 mg/kg i.p.) improved PPI in all three strains, with order of effect in DBA/2J > 129S6SvEvTac > C57Bl/6J. The DBA/2J strain showed larger PPI-enhancing effects, without disturbing the basal startle response. Two alpha7 nicotinic receptor agonists, GTS-21 (1-10 mg/kg i.p.) and AR-R17779 (1-10 mg/kg i.p.) were inactive in the PPI procedure in DBA/2J mice. DBA/2J mice were very sensitive to the antipsychotic-like effects of atypical (clozapine) and typical (risperidone) antipsychotics, and this strain is proposed as a model to directly measure sensory gating properties of drugs. Alpha7 Nicotinergic receptor agonists were ineffective in this PPI paradigm.
Publisher: Elsevier BV
Date: 08-1992
DOI: 10.1016/0006-8993(92)91176-F
Abstract: The role of endogenous corticotropin-releasing factor (CRF) in the cocaine-induced corticosterone response was investigated by using the immunoneutralization and receptor blockade of endogenous CRF. Pretreatment with different dilutions (1:5, 1:10 and 1:20, i.c.v.) of CRF antibody and different doses of an antagonist for CRF receptors, alpha-helical CRF9-41 (alpha h-CRF, 0.001-1.0 micrograms, i.c.v.), dose-dependently prevented the cocaine-induced increase in corticosterone level. These results support the hypothesis that the activation of the hypothalamo-pituitary-adrenal (HPA) axis by cocaine is mediated through the release of endogenous CRF.
Publisher: Springer Science and Business Media LLC
Date: 02-03-2013
Publisher: FapUNIFESP (SciELO)
Date: 14-12-2012
DOI: 10.1590/S0101-60832012005000007
Abstract: Sintomas psiquiátricos são subjetivos por natureza e tendem a se sobrepor entre diferentes desordens. Sendo assim, a criação de modelos de uma desordem neuropsiquiátrica encontra desafios pela falta de conhecimento dos fundamentos da fisiopatologia e diagnósticos precisos. Modelos animais são usados para testar hipóteses de etiologia e para representar a condição humana tão próximo quanto possível para aumentar nosso entendimento da doença e avaliar novos alvos para a descoberta de drogas. Nesta revisão, modelos animais genéticos e de neurodesenvolvimento de esquizofrenia são discutidos com respeito a achados comportamentais e neurofisiológicos e sua associação com a condição clínica. Somente modelos animais específicos de esquizofrenia podem, em último caso, levar a novas abordagens diagnósticas e descoberta de drogas. Argumentamos que biomarcadores moleculares são importantes para aumentar a tradução de animais a humanos, já que faltam a especificidade e a fidelidade necessárias às leituras comportamentais para avaliar sintomas psiquiátricos humanos.
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.PBB.2013.11.019
Abstract: Oxytocin (OXT) has a plethora of effects on brain function. This review provides a historical overview of the development of research on OXT and drug addiction. By focusing on research that has emerged from our laboratories, we describe how early discoveries of the influence of OXT on learning and memory processes and the emerging conceptualization of addiction as 'pathological learning' have contributed to the demonstration that OXT effectively attenuates long-term neuroadaptation related to opiate and psychostimulant addiction. Through integrating earlier evidence with recent discoveries of the social/affiliative role of OXT, we propose that OXT may interfere with reward and addiction by influencing neurobiological processes involved in stress, learning and memory and social/affiliative behavior.
Publisher: Elsevier
Date: 1993
Publisher: Wiley
Date: 08-1999
DOI: 10.1046/J.1471-4159.1999.0730647.X
Abstract: Monoamine oxidase (MAO) B is considered a key enzyme in dopamine metabolism. The present studies, conducted in MAO B knockout mice, show that lack of MAO B does not alter extracellular levels of dopamine in striatum. Similarly, the synthesis, storage, uptake, and release of dopamine are also unaltered. However, autoradiography revealed a significant up-regulation of the D2-like dopamine receptors in the striatum of MAO B knockout mice. Mutant mice also exhibit a functional supersensitivity of D1-dopamine receptors in the nucleus accumbens. Thus, the agonist SKF 38,393-induced c-Fos immunoreactivity was significantly increased in knockout mice as compared with wild-type controls. In view of the apparently normal basal dopamine dynamics observed in MAO B knockout mice, we hypothesize that a dopamine-independent mechanism underlies adaptations in dopamine receptor function that occur as a consequence of MAO B depletion. Finally, these findings suggest that chronic administration of MAO inhibitors, as occurs in the treatment of Parkinson's disease and depression, may be associated with an increased responsiveness of CNS neurons to dopamine receptor ligands.
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: 2020
Publisher: Elsevier BV
Date: 1992
DOI: 10.1016/0024-3205(92)90151-E
Abstract: The role of endogenous CRF in the locomotor hyperactivity induced by cocaine was investigated by using the immunoneutralization of endogenous CRF and an antagonist of CRF-receptors (alpha-helical CRF9-41: alpha h-CRF) in rats. Different dilutions of anti-CRF antibody (1:5, 1:20, but not 1:100) injected intracerebroventricularly (i.c.v.) 24 hours before the cocaine treatment blocked the expression of locomotor hyperactivity. Pretreatment with different doses (0.001, 0.01, 0.1, 1.0 micrograms i.c.v.) of alpha h-CRF inhibited the locomotor hyperactivity induced by cocaine dose-dependently. Neither the immunoneutralization nor the receptor blockade for CRF changed the hyperactivity induced by another locomotor stimulant caffeine. These results serve as indirect in vivo evidence of the selective role of endogenous CRF in the cocaine-induced behavioral alterations. The findings have implications as concerns the possible role of CRF in human psychopathological changes induced by cocaine.
Publisher: Elsevier BV
Date: 05-2021
Publisher: Elsevier BV
Date: 07-1993
DOI: 10.1016/0006-8993(93)90224-B
Abstract: Corticotropin-releasing factor (CRF) may mediate some of the neuroendocrine and behavioral responses to cocaine. In this study, the distribution of CRF-like immunoreactivity (CRF-LI) was determined in the hypothalamus and in several extrahypothalamic brain regions after acute cocaine administration in handled rats. CRF-LI decreased dose-dependently with cocaine administration in the hypothalamus and in the basal-forebrain structures. A small dose of cocaine (7.5 mg/kg) decreased CRF-LI in the hippoc us and in the frontal cortex. A significant, selective, dose-dependent increase in CRF-LI was found in the amygdala after cocaine injection. None of the investigated doses of cocaine altered CRF-LI in the striatum. These results suggest that acute cocaine administration alters brain CRF systems to contribute behavioral and neuroendocrine responses to cocaine.
Publisher: Springer Science and Business Media LLC
Date: 29-08-2017
DOI: 10.1038/TP.2017.190
Publisher: Elsevier BV
Date: 10-1992
DOI: 10.1016/0091-3057(92)90182-F
Abstract: Subchronic administration of cocaine induces behavioral sensitization (increasing hypermotility) to a challenge dose of the drug administered 72 h after the cessation of treatment. The effects of repeated administration of the neurohypophyseal hormones oxytocin (OXT) and arginine8-vasopressin (AVP) on the development of behavioral sensitization induced by subchronic treatment with cocaine were investigated in mice. Repeated treatment of OXT and AVP did not modify the locomotor stimulatory effect of the challenge dose of cocaine in cocaine-naive control animals. OXT in a dose of 0.5 microgram (sc) augmented the cocaine-induced behavioral sensitization. In contrast, AVP (0.005-0.5 microgram/mouse, sc) dose dependently attenuated the development of sensitization to the hypermotility-inducing effect of cocaine. The results suggest that the behavioral sensitization induced by cocaine can be modulated in opposite directions by neurohypophyseal hormones.
Publisher: Wiley
Date: 19-09-2011
Publisher: Elsevier BV
Date: 11-1998
DOI: 10.1016/S0306-4530(98)00064-X
Abstract: Neuropeptides affect adaptive central nervous system processes related to opiate ethanol and cocaine addiction. Oxytocin (OXT), a neurohypophyseal neuropeptide synthesized in the brain and released at the posterior pituitary, also is released in the central nervous system (CNS). OXT acts within the CNS and has been shown to inhibit the development of tolerance to morphine, and to attenuate various symptoms of morphine withdrawal in mice. In rats, intravenous self-administration of heroin was potently decreased by OXT treatment. In relation to cocaine abuse, OXT dose-dependently decreased cocaine-induced hyperlocomotion and stereotyped grooming behavior. Following chronic cocaine treatment, the behavioral tolerance to the sniffing-inducing effect of cocaine was markedly inhibited by OXT. Behavioral sensitization to cocaine, on the other hand, was facilitated by OXT. OXT receptors in the CNS--mainly those located in limbic and basal forebrain structures--are responsible for mediating various effects of OXT in the opiate- and cocaine-addicted organism. Dopaminergic neurotransmission--primarily in basal forebrain structures--is another important biochemical mediator of the central nervous system effects of OXT. Tolerance to ethanol (e.g. hypothermia-inducing effect of ethanol) also was inhibited by OXT.
Publisher: SAGE Publications
Date: 02-10-2015
Abstract: Mental health, well-being, and social life are intimately related as is evident from the higher incidence of psychiatric illness in in iduals exposed to social stress and adversity. Several biological pathways linking social adversity to health outcomes are heavily investigated in the aims of facilitating early identification and prevention of adverse health outcomes. We provide a practice-orientated overview of the allostatic load model and how it relates to metabolic and cardiovascular comorbidity in psychiatric disorders. Allostatic load brings together a set of neuroendocrine, metabolic, immune and cardiovascular biomarkers that are elevated in in iduals with adverse early life experiences and are predictive of cardiovascular and metabolic risk in psychiatric illness of critical importance for Indigenous Australians.
Publisher: Elsevier BV
Date: 09-1992
DOI: 10.1016/0143-4179(92)90006-I
Abstract: The effects of acute and chronic cocaine treatments on the levels of the neurohypophyseal hormones oxytocin (OXT) and vasopressin (AVP) in the plasma and in different brain structures in rats were measured by radioimmunoassay (RIA). Acute cocaine treatment had no effect on the level of OXT in the plasma or in the amygdala, but increased OXT contents were measured in the hypothalamus and in the hippoc us. The OXT levels in the basal forebrain structures (including the septum and the nucleus accumbens) were decreased by a single dose of cocaine. The acute injection of cocaine increased the level of AVP in the plasma, and decreased contents of OXT were measured in the amygdala and in the basal forebrain. Repeated treatment with cocaine decreased the level of OXT in the plasma, hypothalamus and hippoc us. The AVP contents were decreased in all of the brain structures investigated, but no change was caused in the plasma level of AVP by repeated injections of cocaine. These results demonstrate complex, region-specific interactions between cocaine and the neurohypophyseal hormones in the brain and in the periphery underlying the alteration in behavioral and autonomic functions caused by acute and chronic cocaine exposure.
Publisher: American Medical Association (AMA)
Date: 03-2013
DOI: 10.1001/2013.JAMAPSYCHIATRY.86
Abstract: Evidence for symptomatic convergence of schizophrenia and N-methyl-D-aspartate glutamate receptor (NMDA-R) encephalitis highlights the need for an assessment of antibody prevalence and specificity for distinct disease mechanisms in patients with a diagnosis of schizophrenia among glutamatergic pathophysiologic abnormalities in psychiatric disorders. To compare the specificity and prevalence of NMDA-R antibodies in schizophrenia (DSM-IV criteria) with those of other psychiatric diagnoses and to determine whether antibody subtypes characterize overlap with and distinction from those in NMDA-R encephalitis. Serum from 459 patients admitted with acute schizophrenia, major depression (MD), and borderline personality disorder (BLPD) or in iduals serving as matched controls was obtained from our scientific blood bank. To explore epitope specificity and antibody subtype, IgA/IgG/IgM NMDA-R (NR1a or NR1a/NR2b) and α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptors (AMPA-R) (GluR1/GluR2) serum antibodies were determined. Two hundred thirty matched healthy controls were compared with patients (unmedicated for at least 6 weeks) with schizophrenia (n = 121), MD (n = 70), or BLPD (n = 38). The primary outcome was the overall number of seropositive cases for NMDA-R and AMPA-R antibodies the secondary outcome was disease specificity of IgA/IgG/IgM antibodies and epitope specificity for clinical subgroups. Diverse NMDA-R antibodies were identified in 15 subjects, primarily those with an initial schizophrenia diagnosis (9.9%), opposed to MD (2.8%), BLPD (0), and controls (0.4%). Retrospectively, 2 patients initially classified as having catatonic or disorganized schizophrenia were reclassified as having misdiagnosed NMDA-R encephalitis (presence of specific serum and cerebrospinal fluid IgG NR1a antibodies). In all other seropositive cases, the antibodies consisted of classes IgA and/or IgM or were directed against NR1a/NR2b (not against NR1a alone). None of the patients or controls had antibodies against AMPA-R. Acutely ill patients with an initial schizophrenia diagnosis show an increased prevalence of NMDA-R antibodies. The repertoire of antibody subtypes in schizophrenia and MD is different from that with NMDA-R encephalitis. The latter disorder should be considered as a differential diagnosis, particularly in young females with acute disorganized behavior or catatonia.
Publisher: Elsevier BV
Date: 2023
Publisher: Wiley
Date: 11-10-2007
Publisher: Springer Science and Business Media LLC
Date: 16-02-2011
DOI: 10.1007/S00406-011-0197-3
Abstract: Magnetic resonance imaging and postmortem studies on schizophrenia provided evidence for compromised myelin integrity and reduced numbers of oligodendrocytes, which may worsen during the disease course. However, it is not clear whether these findings result from disease-inherent oligodendrocyte degeneration or side effects of antipsychotic treatment. Therefore, effects of haloperidol and clozapine on the viability and apoptosis of immature oligodendrocytes (OLN-93 cells, immunopositive for NG2, Olig1, Olig2) have been evaluated in the present study by labeling with propidium iodide and a caspase 3 assay. Given the indications for impaired cerebral energy supply in schizophrenia, a serum and glucose deprivation (SGD) model was chosen in comparison with the basal condition (BC). SGD led to increased necrotic and apoptotic cell death. Haloperidol and clozapine were partially protective in this model and reduced the percentage of propidium iodide-positive cells, while caspase 3 activity was not altered. No significant drug effects were observed under BC. The observed protective effects of haloperidol and clozapine on energy-deprived OLN-93 oligodendrocytes suggest that previously reported reductions in oligodendrocyte density in schizophrenia are rather disease related than a side effect of medication. A new mechanism of antipsychotic action is suggested, which may help to establish new oligodendrocyte-directed therapies of schizophrenia.
Publisher: Elsevier BV
Date: 06-2009
DOI: 10.1016/J.BRAINRES.2009.04.031
Abstract: Multidrug efflux transporters protect cells in the brain from potentially harmful substances but also from therapeutically useful drugs. Thus any condition that causes changes in their expression is of some importance with regard to drug access. In this study, changes in efflux transporter expression are investigated in mice containing a mutant constitutively active glycogen synthase kinase-3 (GSK-3beta) transgene, driven by the Thy-1 promoter so limiting its localization predominantly to neurons and some glial cells. As expected, decreases in beta-catenin were evident via Western blot analyses of cortical homogenates prepared from brains of these transgenic mice. As assessed by real time qRT-PCR, decreased transcript levels of the mdr1b isoform of P-glycoprotein, Mrp1 and Mrp4, (transporters associated with neurons and/or glial cells) were observed in the cortex but not the subventricular zone or hippoc us of the transgenic compared to wild type mouse brains. By contrast, no such decreases were evident with the mdr1a isoform of P-glycoprotein and Bcrp, transporters predominantly found in brain endothelium. Such transporter expression changes could not be accounted for by alterations in blood vessel density or neuronal to glial cell ratios as analyzed both from immunocytochemical staining and from RT-PCR. These observations support previous in vitro data showing that manipulations to GSK-3beta activity that alter signaling via beta-catenin can influence the expression of efflux transporters. Implications from this are that drug distribution into cells within the brain of these transgenic mice could be enhanced, hence warranting further investigation.
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.BBR.2014.04.016
Abstract: Schizophrenia is a chronic, debilitating disorder with a complex behavioral and cognitive phenotype underlined by a similarly complex etiology involving an interaction between susceptibility genes and environmental factors during early development. Limited progress has been made in developing novel pharmacotherapy, partly due to a lack of valid animal models. The recent recognition of the potentially causal role of central and peripheral energy metabolism in the pathophysiology of schizophrenia raises the need of research on animal models that combine both behavioral and metabolic phenotypic domains, similar to what have been identified in humans. In this review we focus on selected genetic (DBA/2J mice, leptin receptor mutants, and PSD-93 knockout mice), early neurodevelopmental (maternal protein deprivation) and pharmacological (acute phencyclidine) animal models that capture the combined behavioral and metabolic abnormalities shown by schizophrenic patients. In reviewing behavioral phenotypes relevant to schizophrenia we apply the principles established by the Research Domain Criteria (RDoC) for better translation. We demonstrate that etiologically erse manipulations such as specific breeding, deletion of genes that are primarily involved in metabolic regulation and in synaptic plasticity, as well as early metabolic deprivation and adult pharmacological challenge of the glutamate system can lead to schizophrenia-related behavioral and metabolic phenotypes, which suggest that these pathways might be interlinked. We propose that using animal models that combine different domains of schizophrenia can be used as a translationally valid approach to capture the system-level complex interplay between peripheral and central processes in the development of psychopathology.
Publisher: Elsevier BV
Date: 2021
DOI: 10.1016/J.PSYNEUEN.2020.104903
Abstract: Cortisol is the primary glucocorticoid produced by the activation of the hypothalamic pituitary adrenal (HPA) axis after a psychological or physiological stressor. The dysregulation of the HPA axis by chronic stress has been associated with psychiatric disorders. Although hair is currently the main validated source of chronic cortisol concentrations, cortisol is also bound to human nails, another keratinised matrix. Therefore, nail cortisol has the potential to be an alternative retrospective chronic measure of HPA activation. The aim of this systematic review was to assess the temporal resolution, methodological issues, HPA correlates, and target populations in nail cortisol investigations. A qualitative synthesis was performed to assess current literature exploring cortisol concentrations from human nails. A total of 18 eligible human studies extracted from Medline (PubMed and Ovid), ProQuest (PsycINFO), and Scopus found that immunoassays and mass spectrometry were the two primarily methods of analysis. However, methodological variability remained evident between studies. Nail cortisol correlated with saliva and hair in some studies and was investigated across multiple developmental periods. Finally, when applied as an outcome measure in health disorders, higher nail cortisol concentrations have been shown to be associated with acute coronary syndrome and depression. In conclusion, nail cortisol may serve as a retrospective biomarker of chronic stress however, the ability to track how much cortisol is accumulating within nail clippings is complex and may represent a large timespan. Further, very few studies have reported effect sizes and investigated the effects of covariates, such as age, sex, ethnicity, and nail characteristics, which limits the validation of this measure. Further studies are required to validate the utility of nail cortisol as a biomarker of chronic stress across the human lifespan.
Publisher: Elsevier
Date: 1999
DOI: 10.1016/S0079-6123(08)61587-3
Abstract: Oxytocin (OT) has been implicated in neuroadaptive processes such as learning, memory, and social-affiliative behavior as well as in the regulation of physiological responses leading to adaptation to the changing external and internal environment. Drugs of abuse constitute a major challenge to the homeostasis of the body and behavior. Drug tolerance, dependence and addiction may involve neuroadaptive mechanisms related to learning and memory at cellular and systems levels. Considerable effort has been made toward the understanding the neurobiological mechanisms of addictive behavior. Neuropeptides OT and vasopressin (VP) might be involved in these processes based on their effects on neuroadaptation and on their neuroanatomical localization and pharmacological actions. It has been demonstrated that both OT and VP have modulatory effects on opiate and alcohol tolerance and dependence. This chapter summarize the effects of OT, and in lesser extent VP, on neuroadaptation to cocaine, a psychostimulant drug of abuse. We have shown that OT inhibits acute cocaine-induced locomotor hyperactivity, exploratory activity and stereotyped behavior in rodents. Furthermore, OT facilitated, whereas VP inhibited the development of behavioral sensitization to cocaine. In a different model, OT inhibited the development of tolerance to the stereotyped behavior-inducing effects of cocaine as well as cocaine intravenous self-administration in rats. We demonstrated that OT acts through its specific receptors in the basal forebrain and in the hippoc us. OT and VP contents in the hypothalamus and limbic structures were altered by acute and chronic cocaine administration in a dose-dependent and region-selective manner. The differential plasticity of the brain OT-ergic and VP-ergic neurotransmissions in response to cocaine may underlie the differences in the involvement of these neuropeptides in cocaine addiction. Interaction of OT with dopaminergic neurotransmission in the nucleus accumbens, a key brain structure in drug addiction, as well as OT-ergic regulation of hippoc al processes may be among the mechanisms of action through which OT modulates neuroadaptation to cocaine. A better understanding of the role of OT in neuroadaptation to cocaine may provide an insight into both the mechanisms of neuropeptide actions in the brain as well as into the neurobiology of drug addiction.
Publisher: No publisher found
Date: 1991
DOI: 10.1016/0031-9384(91)90541-U
Abstract: The bilateral injection of the oxytocin receptor antagonist, N-acetyl-2-O-methyl-tyrosine-oxytocin (AMTO), in the nucleus accumbens of male rats prevented oxytocin-enhanced grooming without affecting locomotor activity. This effect was dose related. Oxytocin infusions did not alter open field activity. The present study investigated whether oxytocin receptors in the nucleus accumbens are essential for the expression of grooming enhanced by the neuropeptide.
Publisher: Elsevier BV
Date: 04-2015
DOI: 10.1016/J.EJPHAR.2014.07.050
Abstract: Stress, through corticotropin-releasing factor (CRF), influences all aspects of cocaine addiction. Earlier studies suggest that in idual differences in responsivity to stress affect susceptibility to develop addiction. We have previously found that CRF over-expression alters in idual differences in behavioural responses to novelty stress in mice. Therefore, we hypothesised that post-natal, long-term over-expression of brain CRF may alter the rewarding effects of cocaine in a manner that is sensitive to in idual differences. In this study we specifically investigated cocaine-induced conditioned place preference (CPP) in transgenic mice over-expressing CRF (CRF-OE) and in wild-type (WT) littermates after determining their in idual locomotor and emotional responsivity to inescapable novelty. CRF-OE mice showed decreased overall locomotor activity and increased anxiety-like behaviour in response to novelty compared to WT mice. Low behavioural reactivity to novelty (LR) was associated with heightened anxiety-like behaviour in CRF-OE, but not in WT, mice. WT and CRF-OE mice developed CPP equally to both low (5mg/kg) and high (20mg/kg) doses of cocaine. However, LR CRF-OE mice expressed significantly stronger cocaine CPP than transgenic mice with high locomotor response to novelty (HR). In WT mice, on the other hand, stronger CPP induced by 20mg/kg of cocaine was found in the HR animals. Furthermore, there was a strong negative correlation between locomotor reactivity to novelty and CPP in CRF-OE, but not in WT, mice. Collectively, these results suggest that long-term, post-natal CRF over-expression increases the rewarding effects of cocaine in in iduals with high emotional response to stress.
Publisher: Wiley
Date: 04-03-2011
Publisher: Informa UK Limited
Date: 03-03-2020
Publisher: Springer Science and Business Media LLC
Date: 31-03-2009
Publisher: Springer Science and Business Media LLC
Date: 31-01-2017
DOI: 10.1038/SREP41760
Abstract: First Nations people globally have a higher incidence of mental disorders and non-communicable diseases. These health inequalities are partially attributed to a complex network of social and environmental factors which likely converge on chronic psychosocial stress. We hypothesized that alterations in stress processing and the regulation of the hypothalamic-pituitary-adrenal axis might underlie health disparities in First Nations people. We assessed the cortisol awakening response and the dynamic response to a laboratory induced psychosocial stress of young Indigenous tertiary students (n = 11, mean age 23.82 years) and non-Indigenous students (n = 11) matched for age and gender. Indigenous participants had a blunted cortisol awakening response (27.40 (SD 35.00) vs. 95.24 (SD 55.23), p = 0.002), which was differentially associated with chronic experience of stress in Indigenous (r = −0.641, p = 0.046) and non-Indigenous (r = 0.652, p = 0.03) participants. The cortisol response to the laboratory induced psychosocial stress did not differ between groups. Self-reported racial discrimination was strongly associated with flattened cortisol response to stress (r = −0676, p = 0.022) and with heart rate variability (r = 0.654, p = 0.040). Our findings provide insight into potential biological factors underlying health discrepancies in ethnic minority groups.
Publisher: Informa UK Limited
Date: 05-03-2019
DOI: 10.1080/10253890.2019.1572745
Abstract: Chronic stress and adversity are associated with poor mental health and are thought to contribute to the existing mental health gap between Aboriginal and Torres Strait Islander people and other Australians. Hair cortisol and allostatic load (AL) are indices of sustained stress and may be mediators of the effects of stress on health. The aim of this study was to examine the relationship between hair cortisol, AL, and depressive symptoms. This cross-sectional study comprised 329 Aboriginal and Torres Strait Islander adolescents and adults recruited at two health screening programs operating in three communities in north Queensland. We measured hair cortisol and calculated an AL index from 10 biomarkers. We assessed depressive symptoms with a version of the Patient Health Questionnaire-9 adapted for Aboriginal and Torres Strait Islander people (aPHQ-9). We found differences in cortisol and AL between the screening programs and communities, which were not explained by depressive symptoms. Overall aPHQ-9 scores were unrelated to hair cortisol (p = .25 and p = .94) and AL (p = .30 and p = .88) when age, gender and smoking were taken into account. However, anhedonia (p = .007) and insomnia (p = .006) sub-scores were each significantly associated with AL in one study site. Our present data did not demonstrate overall associations of stress biomarkers and multisystem dysregulation with depressive symptoms, which suggests that the relationship between cumulative stress and depression may be better explained by other factors in this population. The specific association between anhedonia and insomnia with AL indicates that chronic multisystem dysregulation plays a role in these features of depression in this population. Lay summary Our study investigated the relationship between symptoms of depression and two biological pathways thought to mediate depression risk - the stress hormone cortisol and allostatic load (AL) - in an Australian Aboriginal and Torres Strait Islander population. Overall, cortisol and AL were unrelated to depression. However, AL was selectively associated with anhedonia (lack of motivation or drive) and sleep disturbances. These results suggest that metabolic dysregulation measured as AL may be relevant to the depression risk in this population.
Publisher: Elsevier BV
Date: 03-1993
Publisher: Springer US
Date: 2020
Publisher: Springer New York
Date: 2018
DOI: 10.1007/978-1-4939-7614-0_28
Abstract: Early parental nutritional interventions during prenatal development have been shown to result in neuropsychiatric sequelae in the adult offspring. In order to understand the impact of such nutritional interventions, the behavior of the animal has to be carefully analyzed. This chapter provides a step-by-step guide to conduct behavioral tests in adult mice for investigators without specific expertise or those without the equipment to carry out behavioral studies. We focus on tests tapping into the main behavioral abnormalities that correspond to mental illnesses. We describe the materials required and the detailed methods to conduct global assessment of parameters such as behavioral integrity and general well-being, psychomotor activity, social behavior, repetitive behavior, anxiety-like behavior, depression-like behavior, short-term spatial working memory, and spatial reference memory.
Publisher: Informa UK Limited
Date: 28-06-2011
DOI: 10.3109/15622975.2011.583941
Abstract: Previous studies have suggested that the pathogenesis of schizophrenia and major depression involves an altered peripheral immune system. It is not clear, however, whether such changes are associated with corresponding neuroinflammatory responses and disturbances of neurotransmission. This paper reviews the current state of knowledge about the involvement of immune alterations in schizophrenia and major depression and a possible link to disturbances of glutamatergic transmission. Inflammatory endogenous modulators of the NMDA receptor, the kynurenine pathway metabolites, are potential candidates for such a link. Studies of the blood and cerebrospinal fluid have suggested a schizophrenia-related upregulation of the NMDA receptor antagonist kynurenic acid in astrocytes, analogous to the ketamine psychosis model. Conversely, it has been proposed that there is depression-related microglial synthesis of the NMDA receptor agonist quinolinic acid, which is consistent with the observation that ketamine has therapeutic effects in major depression. Few publications have studied NMDA receptor modulating kynurenines in the brain, however. Future research on the cerebral cell-type specific distribution of kynurenine metabolites and their brain-regional concentration imbalances will be required to connect peripheral immune changes, the hypotheses of blood-brain barrier dysfunction and glial pathology with concepts of altered neurotransmission in schizophrenia and major depression.
Publisher: The Royal Society
Date: 27-01-2010
Abstract: Little is known about the role of the endocrine system in financial decision-making. Here, we survey research on steroid hormones and their cognitive effects, and examine potential links to trader performance in the financial markets. Preliminary findings suggest that cortisol codes for risk and testosterone for reward. A key finding of this endocrine research is the different cognitive effects of acute versus chronic exposure to hormones: acutely elevated steroids may optimize performance on a range of tasks but chronically elevated steroids may promote irrational risk-reward choices. We present a hypothesis suggesting that the irrational exuberance and pessimism observed during market bubbles and crashes may be mediated by steroid hormones. If hormones can exaggerate market moves, then perhaps the age and sex composition among traders and asset managers may affect the level of instability witnessed in the financial markets.
Publisher: S. Karger AG
Date: 1998
DOI: 10.1159/000054382
Abstract: Acute cocaine administration activates behavioral and neuroendocrine processes associated with the stress response. However, much less is known about the effects of chronic, long-term cocaine administration on neuroendocrine adaptations and in idual vulnerability to stress. We hypothesized that chronic ‘binge’ cocaine administration may serve as a chronic pharmacological stressor leading to a hyperactivity of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis and alterations in its feedback mechanisms. In order to test this hypothesis, the effects of long-term (3 and 6 weeks) ‘binge’ pattern cocaine administration (3×15 mg/kg cocaine, i.p., daily, during the early phase of the light cycle) on body weight, adrenal gland weight, basal and stress-induced activity of the corticosterone (CORT) and basal plasma testosterone (T) levels were measured. Both 3 and 6 weeks ‘binge’ cocaine administration decreased body weight gain, increased the weight of adrenal glands and increased basal CORT levels. Plasma T levels were suppressed by both 3 and 6 weeks of cocaine treatment. No correlation was found between elevated CORT and low T levels at any time point. Neither chronic saline nor cocaine administration altered stress-induced CORT secretion. CORT levels 60 min following the restraint stress (recovery) were significantly lower than pre-stress basal levels after 3 and 6 weeks of cocaine, but not saline, administration. Moreover, initial in idual differences in stress-induced CORT response, i.e. low and high responsivity to restraint prior to any saline or cocaine injections, were maintained in control rats but became diminished in cocaine-treated rats. These results indicate that chronic binge cocaine administration leads to sustained activation of the HPA axis and alters processes underlying in idual vulnerability to stress.
Publisher: Springer Science and Business Media LLC
Date: 28-01-2020
DOI: 10.1007/S00213-020-05467-2
Abstract: Impaired cerebral glucose metabolism is a core pathological feature of schizophrenia. We recently demonstrated that a ketogenic diet, causing a shift from glycolysis to ketosis, normalized schizophrenia-like behaviours in an acute N-methyl-D-aspartate (NMDA) receptor antagonist model of the illness. Ketogenic diet produces the ketone body, β-hydroxybutyrate (BHB), which may serve as an alternative fuel source in its own right without a strict dietary regime. We hypothesized that chronic administration of BHB replicates the therapeutic effects of ketogenic diet in an acute NMDA receptor hypofunction model of schizophrenia in mice. C57Bl/6 mice were either treated with acute doses of 2 mmol/kg, 10 mmol/kg, or 20 mmol/kg BHB or received daily intraperitoneal injections of 2 mmol/kg BHB or saline for 3 weeks. Behavioural testing assessed the effect of acute challenge with 0.2 mg/kg MK-801 or saline on open field behaviour, social interaction, and prepulse inhibition of startle (PPI). Acute BHB administration dose-dependently increased BHB plasma levels, whereas the 2 mmol/kg dose increased plasma glucose levels. The highest acute dose of BHB supressed spontaneous locomotor activity, MK-801-induced locomotor hyperactivity and MK-801-induced disruption of PPI. Chronic BHB treatment normalized MK-801-induced hyperlocomotion, reduction of sociability, and disruption of PPI. In conclusion, BHB may present a novel treatment option for patients with schizophrenia by providing an alternative fuel source to normalize impaired glucose metabolism in the brain.
Publisher: Elsevier BV
Date: 09-1992
DOI: 10.1016/0091-3057(92)90656-Z
Abstract: The development of cross-tolerance to an analgesic effect has been observed between a mu-receptor agonist, heroin, and a delta-receptor agonist, Met2-Pro5-enkephalinamide. Repeated treatments with heroin twice a day for 4 days resulted in a decreased nociceptive effect to enkephalin on day 5. The enkephalin dose-response line was shifted to the right, considered a sign of the development of cross-tolerance. Peripheral treatment with oxytocin blocked the development of heroin-enkephalin cross-tolerance. A similar effect was observed after intracerebroventricular administration of oxytocin, supporting our assumption that oxytocin blocks the development of heroin-enkephalin cross-tolerance via CNS mechanisms.
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.PSYNEUEN.2022.105726
Abstract: Psychiatric disorders are complex, disabling, and chronic conditions that are often accompanied by one or more systemic medical comorbidities. In this narrative review, we provide an overview of the allostatic load concept, which represents a multi-system dysregulation in response to chronic stress and link it to systemic comorbidities associated with psychiatric disorders. We synthesized published literature gathered using Medline (Ovid), Scopus, and PsychInfo and identified a high frequency of systemic comorbidities for both mood and psychotic disorders. The identified cardiovascular, metabolic, and immune comorbidities may represent the result of chronic wear and tear caused by a complex interaction between chronic psychosocial stress, health risk behaviors, pharmacological stressors, and the biological systems involved in the development of allostatic load. These findings support the notion that psychiatric disorders should be re-conceptualized as systemic disorders, affecting the brain and systemic biological pathways in an interconnected fashion to result in systemic comorbidities. We suggest that the multi-systemic and multi-dimensional approach that drives the allostatic load concept should be considered for understanding comorbidities in vulnerable psychiatric patients.
Publisher: Public Library of Science (PLoS)
Date: 27-03-2019
Publisher: Informa UK Limited
Date: 29-12-2015
DOI: 10.3109/10253890.2014.989204
Abstract: Ethnic minority groups across the world face a complex set of adverse social and psychological challenges linked to their minority status, often involving racial discrimination. Racial discrimination is increasingly recognized as an important contributing factor to health disparities among non-dominant ethnic minorities. A growing body of literature has recognized these health disparities and has investigated the relationship between racial discrimination and poor health outcomes. Chronically elevated cortisol levels and a dysregulated hypothalamic-pituitary-adrenal (HPA) axis appear to mediate effects of racial discrimination on allostatic load and disease. Racial discrimination seems to converge on the anterior cingulate cortex (ACC) and may impair the function of the prefrontal cortex (PFC), hence showing substantial similarities to chronic social stress. This review provides a summary of recent literature on hormonal and neural effects of racial discrimination and a synthesis of potential neurobiological pathways by which discrimination affects mental health.
Publisher: SAGE Publications
Date: 08-12-2016
Abstract: A considerable gap exists in health and social emotional well-being between Indigenous people and non-Indigenous Australians. Recent research in stress neurobiology highlights biological pathways that link early adversity and traumas as well as life stresses to ill health. We argue that the neurobiological stress response and its maladaptive changes, termed allostatic load, provide a useful framework to understand how adversity leads to physical and mental illness in Indigenous people. In this paper we review the biology of allostatic load and make links between stress-induced systemic hormonal, metabolic and immunological changes and physical and mental illnesses. Exposure to chronic stress throughout life results in an increased allostatic load that may contribute to a number of metabolic, cardiovascular and mental disorders that shorten life expectancy in Indigenous Australians.
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.SCHRES.2018.11.011
Abstract: Recent transcriptomic, proteomic and metabolomics studies have highlighted an abnormal cerebral glucose and energy metabolism as one of the potential pathophysiological mechanisms of schizophrenia. This raises the possibility that a metabolically-based intervention might have therapeutic value in the management of schizophrenia, a notion supported by our recent results that a low carbohydrate/high-fat therapeutic ketogenic diet (KD) prevented a variety of behavioural abnormalities induced by pharmacological inhibition of NMDA glutamate receptors. Here we asked if the beneficial effects of KD can be generalised to impaired prepulse inhibition of startle (PPI), a translationally validated endophenotype of schizophrenia, in a pharmacological model in mice. Furthermore, we addressed the issue of whether the effect of KD is linked to the calorie-restricted state typical of the initial phase of KD. We fed male C57BL/6 mice a KD for 7 weeks and tested PPI at 3 and 7 weeks, in the presence and absence of a significant digestible energy deficit, respectively. We used an NMDA receptor hypo-function model of schizophrenia induced by acute injection of dizocilpine (MK-801). We found that KD effectively prevented MK-801-induced PPI impairments at both 3 and 7 weeks, irrespective of the presence or absence of digestible energy deficit. Furthermore, there was a lack of correlation between PPI and body weight changes. These results support the efficacy of the therapeutic KD in a translational model of schizophrenia and furthermore provide evidence against the role of calorie restriction in its mechanism of action.
Publisher: Springer Science and Business Media LLC
Date: 14-12-2012
DOI: 10.1007/S00406-011-0282-7
Abstract: Protein expression of VGF (nonacronymic) is induced by nerve/brain-derived growth factor, neurotrophin 3, and insulin. VGF is synthesized by neurons in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus. After enzymatic processing, smaller VGF-derived peptides are secreted into the cerebrospinal fluid (CSF) or blood. These peptides play important roles by improving synaptic plasticity, neurogenesis, and energy homeostasis, which are impaired in schizophrenia. Based on previous observations of neuroendocrine and hypothalamic deficits in schizophrenia and to determine whether increased levels of the VGF fragment 23-62 in CSF, which have been described in a recent study, were related to changes in hypothalamic VGF expression, an immunohistochemical study was performed in 20 patients with schizophrenia and 19 matched control subjects. N- (D-20) and C-terminal (R-15) VGF antibodies yielded similar results and immunolabeled a vast majority of PVN and SON neurons. Additionally, D20-VGF immunohistochemistry revealed immunostained fibers in the pituitary stalk and neurohypophysis that ended at vessel walls, suggesting axonal transport and VGF secretion. The cell density of D20-VGF-immunoreactive neurons was reduced in the left PVN (P = 0.002) and SON (P = 0.008) of patients with schizophrenia. This study provides the first evidence for diminished hypothalamic VGF levels in schizophrenia, which might suggest increased protein secretion. Our finding was particularly significant in subjects without metabolic syndrome (patients with a body mass index ≤28.7 kg/m(2)). In conclusion, apart from beneficial effects on synaptic plasticity and neurogenesis, VGF may be linked to schizophrenia-related alterations in energy homeostasis.
Publisher: Springer US
Date: 2020
Publisher: Springer Science and Business Media LLC
Date: 09-03-2022
DOI: 10.1038/S41380-022-01494-X
Abstract: A substantial and erse body of literature suggests that the pathophysiology of schizophrenia is related to deficits of bioenergetic function. While antipsychotics are an effective therapy for the management of positive psychotic symptoms, they are not efficacious for the complete schizophrenia symptom profile, such as the negative and cognitive symptoms. In this review, we discuss the relationship between dysfunction of various metabolic pathways across different brain regions in relation to schizophrenia. We contend that several bioenergetic subprocesses are affected across the brain and such deficits are a core feature of the illness. We provide an overview of central perturbations of insulin signaling, glycolysis, pentose-phosphate pathway, tricarboxylic acid cycle, and oxidative phosphorylation in schizophrenia. Importantly, we discuss pharmacologic and nonpharmacologic interventions that target these pathways and how such interventions may be exploited to improve the symptoms of schizophrenia.
Publisher: Springer International Publishing
Date: 30-09-2017
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.PSYNEUEN.2018.02.001
Abstract: Current pathophysiological models of schizophrenia suggest that stress contributes to the etiology and trajectory of the disorder. We investigated if allostatic load (AL), an integrative index of neuroendocrine, immune and metabolic dysregulation in response to chronic stress, is elevated in patients with schizophrenia (SCZ) and first-episode psychosis (FEP) and related to psychotic symptoms and social and occupational functioning. Additionally, we assessed the temporal dynamics of AL in response to treatment with second-generation antipsychotics. AL, psychotic symptoms and psychosocial functioning were assessed in a longitudinal design in patients with SCZ (n = 28), FEP (n = 28), and healthy controls (n = 53) at baseline and 6 and 12 weeks after commencement of antipsychotic therapy. AL at baseline was higher in patients with SCZ and FEP relative to controls, but not different between patients with SCZ and FEP. Adjusting for age and smoking, we found that positive symptoms were positively correlated with AL and psychosocial functioning was negatively correlated with AL at trend level. Linear mixed model analysis demonstrated that AL decreased after treatment was commenced in patients with SCZ and FEP between the baseline assessment and the 6 and 12-week follow-up. AL was not predictive of treatment response or symptomatic remission. Our data provide evidence for cumulative physiological dysregulation in patients with SCZ and FEP that is linked to the experience of current positive psychotic symptoms. AL could be a useful tool to monitor biological signatures related to chronic stress and unhealthy behaviors in schizophrenia.
Publisher: Springer Science and Business Media LLC
Date: 23-02-2023
DOI: 10.1007/S40670-022-01704-9
Abstract: Deprescribing involves reducing or stopping medications that are causing more harm than good or are no longer needed. It is an important approach to managing polypharmacy, yet healthcare professionals identify many barriers. We present a proposed pre-licensure competency framework that describes essential knowledge, teaching strategies, and assessment protocols to promote interprofessional deprescribing skills. The framework considers how to involve patients and care partners in deprescribing decisions. An action plan and ex le curriculum mapping exercise are included to help educators assess their curricula, and select and implement these concepts and strategies within their programs to ensure learners graduate with competencies to manage increasingly complex medication regimens as people age.
Publisher: American Medical Association (AMA)
Date: 09-2017
Publisher: Oxford University Press (OUP)
Date: 15-02-2018
Abstract: Helminth infections in children are associated with impaired cognitive development however, the biological mechanisms for this remain unclear. Using a murine model of gastrointestinal helminth infection, we demonstrate that early-life exposure to helminths promotes local and systemic inflammatory responses and transient changes in the gastrointestinal microbiome. Behavioral and cognitive analyses performed 9-months postinfection revealed deficits in spatial recognition memory and an anxiety-like behavioral phenotype in worm-infected mice, which was associated with neuropathology and increased microglial activation within the brain. This study demonstrates a previously unrecognized mechanism through which helminth infections may influence cognitive function, via perturbations in the gut-immune-brain axis.
Publisher: Elsevier BV
Date: 06-1992
DOI: 10.1016/0028-3908(92)90192-R
Abstract: Behavioural adaptation to and the effects of the neurohypophyseal peptide, oxytocin, on repeated treatment with cocaine were investigated in rats. The content of immunoreactive oxytocin in the plasma, hypothalamus and different limbic structures in the brain were also studied after treatment with cocaine, identical to that used in the behavioural experiment. Repeated administration of cocaine (7.5 mg/kg, s.c.) produced a behavioural tolerance to the stereotyped sniffing-inducing effect of the challenge doses (1.875, 3.75 and 7.5 mg/kg, s.c.) of cocaine on the fifth day, which was demonstrated by parallel shifting of the dose-response and time-effect curves of the test doses of cocaine. The development of tolerance was inhibited by pretreatment with oxytocin (0.05 micrograms, (s.c.), administered before each daily injection of cocaine. A smaller dose of oxytocin (0.005 micrograms, s.c.) had no effect in this model. A decreased amount of immunoreactive oxytocin was detected in the plasma, in the hypothalamus and in the hippoc us, after repeated treatment with cocaine. Replacement of oxytocin by local injection (100 pg) into the ventral hippoc us, before each daily administration of cocaine, prevented the development of tolerance to cocaine. These results suggest that endogenous oxytocin, localized in limbic-forebrain areas, may have an important regulatory role in the development of behavioural changes induced by the repeated administration of cocaine.
Publisher: Springer International Publishing
Date: 2017
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.NEUBIOREV.2019.12.020
Abstract: Health risk behaviours (HRB) across the lifespan have been associated with higher cumulative physiological burden as measured by allostatic load (AL). This study examines the contribution of HRB and their effects on multisystem biological risk associated with morbidity and early mortality. We systematically reviewed the literature to assess the links between HRB and AL. Twenty-six eligible human studies were included in our assessment of the current literature investigating the association of different HRB that included overeating/obesity, alcohol, smoking, drug use, physical inactivity and sleep impairments in relation to AL. We found that 50 % of obesity and substance abuse, 75 % of sleep and 62.5 % of combined HRB studies showed a significant association with AL. Lifestyle coping behaviours therefore have a significant contribution to AL. This study is among the first to explore multiple domains of HRB in relation to AL. Further research should focus on evaluating lifestyle factors that adapt HRB as a strategy to cope with chronic stress to help decrease AL and resulting long-term negative health consequences.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-1990
DOI: 10.1097/00001756-199011000-00006
Abstract: The effects of pimozide, a dopamine-receptor blocker and oxytocin, a neurohypophyseal neuropeptide were investigated in mice on the cocaine-induced exploratory hyperactivity. The action of oxytocin on changes of dopaminergic neurotransmission induced by cocaine was also measured. Cocaine-induced exploratory hyperactivity could be blocked by pimozide (1 mg kg-1, s.c.). Oxytocin (0.05-1.0 micrograms) inhibited the cocaine-induced hyperactivity in an U-shaped dose-response manner. In the nucleus accumbens, oxytocin antagonized the increased dopamine disappearance, elicited by cocaine, but not in the nucleus caudatus. The data suggest that oxytocin may influence the behavioural effect of cocaine by modulating dopaminergic neurotransmission in mesolimbic dopaminergic terminal region of the brain.
Publisher: Elsevier BV
Date: 12-2020
DOI: 10.1016/J.SCHRES.2018.10.002
Abstract: In iduals at ultra-high risk (UHR) for psychosis have an elevated risk of developing psychosis and other psychiatric outcomes. Risk biomarkers can assist in delineating in idual risk and allow better prediction of longer-term outcomes. The aim of the present study was to examine if allostatic load (AL), a multisystem index of neuroendocrine, cardiovascular, immune and metabolic dysregulation, is associated with clinical outcomes in youth at UHR for psychosis. AL was measured in 106 participants of the NEURAPRO study (n = 70 female, n = 36 male mean age 17.21, SD 2.37), a multicentre randomized-controlled trial of long-chain omega-3 polyunsaturated fatty acids versus placebo in people at UHR for psychosis. Psychiatric symptoms and social and occupational functioning were assessed at baseline and 6 and 12 months after study intake. Multivariate linear and logistic regression models were used to test the relationship between AL and clinical outcomes. High AL at baseline was associated with poor social and occupational functioning at 6 months (β = -0.224, p = 0.025) and with more severe manic symptoms at 6 months (β = 0.207, p = 0.026), taking into account relevant covariates including age and smoking status. No significant associations were observed at the 12-month follow-up assessment or with any other clinical outcome measures. Our data provide initial evidence for a link between AL and impaired functioning in in iduals at UHR for psychosis. Further studies are needed to evaluate AL as a potential predictor of early treatment response.
Publisher: S. Karger AG
Date: 1993
DOI: 10.1159/000126377
Abstract: The possible involvement of endogenous corticotropin-releasing factor (CRF) in the anxiogenic and pituitary-adrenal-axis-activating effects of cholecystokinin octapeptide sulfate ester (CCK 8) was investigated in rats. Intracerebroventricularly (i.c.v.) administered CCK 8 induced an anxiogenic response in an elevated plus-maze test, and enhanced the plasma corticosterone level. Pretreatment with different dilutions (1:10, 1:20 and 1:100, i.c.v.) of CRF antiserum and different doses of a CRF receptor antagonist, alpha-helical CRF (ahCRF, 0.001-1.0 microgram, i.c.v.) prevented the anxiogenic response to CCK 8 in a dose-dependent manner. None of the doses of CRF antiserum or ahCRF alone produced any alteration in either the elevated plus-maze paradigm or corticosterone level in saline-treated control rats. The results strongly suggest that the anxiogenic and hypothalamo-pituitary-adrenal-activating effects of CCK 8 are mediated via CRF.
Publisher: Elsevier BV
Date: 06-1988
DOI: 10.1016/0014-2999(88)90018-0
Abstract: The ability of the selective cyclic mu-opioid receptor antagonist, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), to inhibit the acute and chronic effects of morphine in vivo was studied in mice. Intracerebroventricular (i.c.v.) administration of CTOP antagonized the analgesic effect of morphine in a dose-dependent manner, as measured by the heat-irradiant (tail-flick) method. CTOP was more effective than naloxone in inhibiting analgesia on a molar basis. CTOP also antagonized the acute morphine-induced hypermotility. CTOP caused withdrawal hypothermia and a loss of body weight in morphine-dependent animals. After the development of morphine-induced chronic dependence, CTOP administered i.c.v. caused a dose-dependent loss of body weight and hypothermia, and was about 10-400 times more potent than naloxone. CTOP administered alone to drugnaive mice did not cause antinociception, changes in body weight or body temperature.
Publisher: Proceedings of the National Academy of Sciences
Date: 19-12-2000
Abstract: The hippoc us is a major limbic target of the brainstem serotonergic neurons that modulate fear, anxiety, and learning through postsynaptic serotonin 1A receptors (5-HT 1A receptors). Because chronic stress selectively down-regulates the 5-HT 1A receptors in the hippoc us, we hypothesized that mice lacking these receptors may exhibit abnormalities reminiscent of symptoms of stress-related psychiatric disorders. In particular, a hippoc al deficit in the 5-HT 1A receptor could contribute to the cognitive abnormalities often seen in these disorders. To test whether a deficit in 5-HT 1A receptors impairs hippoc us-related functions, we studied hippoc al-dependent learning and memory, synaptic plasticity in the hippoc us, and limbic neuronal excitability in 5-HT 1A -knockout (KO) mice. 5-HT 1A -KO animals showed a deficit in hippoc al-dependent learning and memory tests, such as the hidden platform (spatial) version of the Morris water maze and the delayed version of the Y maze. The performance of KO mice was not impaired in nonhippoc al memory tasks such as the visible platform (nonspatial) version of the Morris water maze, the immediate version of the Y maze, and the spontaneous-alternation test of working memory. Furthermore, paired-pulse facilitation in the dentate gyrus of the hippoc us was impaired in 5-HT 1A -KO mice. Finally, 5-HT 1A -KO mice, as compared with wild-type animals, displayed higher limbic excitability manifested as lower seizure threshold and higher lethality in response to kainic acid administration. These results demonstrate that 5-HT 1A receptors are required for maintaining normal hippoc al functions and implicate a role for the 5-HT 1A receptor in hippoc al-related symptoms, such as cognitive disturbances, in stress-related disorders.
Publisher: Springer Science and Business Media LLC
Date: 19-01-2019
DOI: 10.1007/S00406-018-0865-7
Abstract: There is evidence for insulin resistance in drug-naïve first-episode schizophrenia (Sz) patients. We have tested whether impaired insulin homeostasis is also present in first-episode patients with major depression (MD) and if this can be discerned from stress-related and medication effects. Homeostatic model assessment of insulin resistance (HOMA-IR) was determined in a cross-sectional cohort study of acute first-episode drug-naïve patients with MD (n = 18) or Sz (n = 24), and healthy controls (C, n = 43). Morning cortisol and catecholamine metabolites were assessed to control for hormonal stress axis activation. Subjects were matched for sex, age, body mass index and waist-hip ratio to exclude the possibility that overweight and visceral adiposity were potential confounding factors. HOMA-IR did not differ between MD and controls, but was increased in Sz compared to MD (p = 0.002) and controls (p = 0.012). Catecholamine metabolites were elevated in both patient groups, indicating presence of hormonal stress axis activation. However, diagnosis-related changes of HOMA-IR were independent from this. Impaired insulin sensitivity was absent in MD, but specifically related to the early disease course of Sz. Thus, considering previous studies in this field, MD may be related to impaired glucose/insulin homeostasis in the long-term but not in early disease stages.
Publisher: Elsevier BV
Date: 02-2021
Publisher: S. Karger AG
Date: 1992
DOI: 10.1159/000126090
Abstract: The effects of cocaine on rat plasma and brain alpha-melanocyte-stimulating hormone (alpha-MSH) levels have been studied by means of a specific radioimmunoassay. The selected brain areas were the hypothalamus, septum-nucleus accumbens and hippoc us. Cocaine given subcutaneously decreased the alpha-MSH levels in the peripheral blood. Pimozide, a dopaminergic antagonist, had an opposite effect: it increased the alpha-MSH levels in the peripheral blood. Combined treatment with cocaine + pimozide resulted in a decrease in the pimozide-induced increase in alpha-MSH levels in the blood. Cocaine and pimozide or the combination of cocaine + pimozide were ineffective on the alpha-MSH levels in the hypothalamus and septum-accumbens brain regions. In the hippoc us, cocaine in the dose applied induced a slight but not significant decrease in the alpha-MSH level. Pimozide caused a significant decrease in the hippoc al alpha-MSH level which disappeared at 60 min. Cocaine prevented the pimozide-induced depletion of alpha-MSH. The data indicate that cocaine may act as a dopaminergic agonist in the mechanism of control of alpha-MSH secretion from the intermediate lobe of the pituitary. The alpha-MSH levels in the brain are controlled by different mechanisms. In some brain areas, the dopaminergic system has no action in others the mechanisms might be similar to but slightly different from that in the pituitary.
Publisher: Frontiers Media SA
Date: 18-11-2014
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.SCHRES.2019.08.002
Abstract: We used the acute NMDA receptor hypoactivity model of schizophrenia in mice to compare the efficacy of a long-term ketogenic diet and a commonly used antipsychotic, olanzapine, and to explore the interaction between these treatments. We found that a ketogenic diet in female mice was as effective as olanzapine to diminish MK-801-induced disruption of prepulse inhibition (PPI). Furthermore, combination of the diet with olanzapine treatment resulted in a similar effect compared to either treatment alone. These results suggest that ketogenic diet can be used effectively together with antipsychotics drugs over an extended period.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.NEUBIOREV.2016.05.027
Abstract: The cortisol awakening response (CAR), defined as the increase in cortisol release in response to waking up, shows associations with social and environmental risk factors of schizophrenia and has been studied as a potential biomarker in schizophrenia. We report a systematic review and meta-analysis of 11 studies and 879 participants focusing on the CAR of patients with schizophrenia, first-episode psychosis, and at-risk mental states. Random-effects meta-analysis showed that CAR is attenuated in patients with psychosis compared to healthy controls (g=-0.426, 95% CI -0.585 to -0.267, p<0.001, 11 between-group comparisons, n=879). Subgroup analysis showed flattened CAR in patients with schizophrenia (g=-0.556, 95% CI -1.069 to -0.044, p<0.05, 2 between-group comparisons, n=114) and first-episode psychosis (g=-0.544, 95% CI -0.731 to -0.358, p<0.001, 6 between-group comparisons, n=505), but not in in iduals with at-risk mental states. These distinctive alterations of hypothalamic-pituitary-adrenal axis function may have important implications for CAR as a marker for transition risk. However, the lack of objective verification of s ling adherence in these studies may limit the interpretation of the results.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2001
DOI: 10.1097/00008877-200111000-00004
Abstract: The 5-HT(1A) receptor has been implicated in the modulation of anxiety processes, mainly via pharmacological experiments. The recent production, in three independent research groups, of 5-HT(1A) receptor knockout (R KO) mice in three different genetic backgrounds (C57BL/6J, 129/Sv, Swiss-Webster) led to the intriguing finding that all mice, independent from the genetic background strain from which the null mutants were made, showed an "anxious" phenotype compared to corresponding wild-type mice. The present paper reviews the behavioral findings in these three KO lines and focuses on new findings in the 129/Sv-KO mice. These mice were more anxious or stress-prone only under specific conditions (high stress) and not as broadly as suggested from the initial studies. The 5-HT(1A) R KO made in the Swiss-Webster background displays disturbances in the GABA(A)-benzodiazepine (BZ) receptor system in the brain, including downregulation of GABA(A) alpha1 and alpha2 subunits in the amygdala. In contrast, the GABA(A)-BZ receptor system seems to function normally in the 5-HT(1A) R KO in the 129/Sv background suggesting that changes in the GABA(A)-BZ receptor system may not be a prerequisite for anxiety but rather could have a modifying effect on this phenotype. It can be concluded that the constitutive absence of the 5-HT(1A) receptor gene and receptor leads to a more "anxious" mouse, dependent on the stress level but independent from the strain. Depending on the genetic background, this null mutation may be associated with changes in GABA(A)-ergic neurotransmission. It is as yet unclear which mechanisms are involved in this intriguing differentiation.
Publisher: Elsevier
Date: 2008
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
Start Date: 07-2023
End Date: 01-2026
Amount: $448,440.00
Funder: Australian Research Council
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