Adolescent alcohol binge drinking and withdrawal: behavioural, brain GFAP-positive astrocytes and acute methamphetamine effects in adult female rats.

RATIONALE: Alcopop beverages are generally the first alcoholic beverage that young females drink which contain high levels of sugar and alcohol. The over-consumption of these drinks may encourage alcohol co-administration with methamphetamine (METH) impacting on drinking behaviour and glial function. AIMS: The aims of this study were to evaluate the effect of adolescent binge alcohol exposure on consumption level, anxiety-like behaviour, cross-sensitization with METH and on astrocyte expression in reward related brain regions. METHODS: Adolescent female Sprague-Dawley rats had daily 1-hour oral alcohol consumption of alcopop (ALCP; with sucrose) or ethanol-only (ETOH; without sucrose), transitioned from 5 to 15% (v/v) ethanol content for 34 days. Water and sucrose groups act as controls. During alcohol withdrawal, rats were tested for anxiety on the elevated plus maze (EPM) and locomotor activity following saline or METH (1 mg/kg i.p) treatment. Brains were then collected to assess astrocyte immunofluorescence for glial fibrillary acidic protein (GFAP) in reward-related brain regions. RESULTS: Rats pretreated with 5% ALCP consumed significantly more volume and ethanol intake when compared to 5% EtOH rats. Both ALCP and EtOH groups had a higher preference ratio for 5% than 15% alcohol solutions and ALCP rats had greater ethanol intake at 15% than EtOH rats. Alcohol withdrawal showed no significant differences between groups on anxiety, METH cross-sensitization effects or GFAP intensity in the regions studied. CONCLUSIONS: Overall, the addition of sucrose to alcoholic solutions encouraged female rats to consume larger volumes and greater ethanol intake compared to ethanol-only solutions, yet did not have long lasting effects on behaviour and astrocytes.

Proteomic Analysis Reveals the Neurotoxic Effects of Chronic Methamphetamine Self-Administration-Induced Cognitive Impairments and the Role of Melatonin-Enhanced Restorative Process during Methamphetamine Withdrawal.

Cognitive flexibility is a crucial ability in humans that can be affected by chronic methamphetamine (METH) addiction. The present study aimed to elucidate the mechanisms underlying cognitive impairment in mice chronically administered METH via an oral self-administration method. Further, the effect of melatonin treatment on recovery of METH-induced cognitive impairment was also investigated. Cognitive performance of the mice was assessed using an attentional set shift task (ASST), and possible underlying neurotoxic mechanisms were investigated by proteomic and western blot analysis of the prefrontal cortex (PFC). The results showed that mice-administered METH for 21 consecutive days exhibited poor cognitive performance compared to controls. Cognitive deficit in mice partly recovered after METH withdrawal. In addition, mice treated with melatonin during METH withdrawal showed a higher cognitive recovery than vehicle-treated METH withdrawal mice. Proteomic and western blot analysis revealed that METH self-administration increased neurotoxic markers, including disruption to the regulation of mitochondrial function, mitophagy, and decreased synaptic plasticity. Treatment with melatonin during withdrawal restored METH-induced mitochondria and synaptic impairments. These findings suggest that METH-induced neurotoxicity partly depends on mitochondrial dysfunction leading to autophagy-dependent cell death and that the recovery of neurological impairments may be enhanced by melatonin treatment during the withdrawal period.

Descending pathways from the superior colliculus mediating autonomic and respiratory effects associated with orienting behaviour.

The ability to discriminate competing external stimuli and initiate contextually appropriate behaviours is a key brain function. Neurons in the deep superior colliculus (dSC) integrate multisensory inputs and activate descending projections to premotor pathways responsible for orienting, attention and defence, behaviours which involve adjustments to respiratory and cardiovascular parameters. However, the neural pathways that subserve the physiological components of orienting are poorly understood. We report that orienting responses to optogenetic dSC stimulation are accompanied by short-latency autonomic, respiratory and electroencephalographic effects in awake rats, closely mimicking those evoked by naturalistic alerting stimuli. Physiological responses were not accompanied by detectable aversion or fear, and persisted under urethane anaesthesia, indicating independence from emotional stress. Anterograde and trans-synaptic viral tracing identified a monosynaptic pathway that links the dSC to spinally projecting neurons in the medullary gigantocellular reticular nucleus (GiA), a key hub for the coordination of orienting and locomotor behaviours. In urethane-anaesthetized animals, sympathoexcitatory and cardiovascular, but not respiratory, responses to dSC stimulation were replicated by optogenetic stimulation of the dSC-GiA terminals, suggesting a likely role for this pathway in mediating the autonomic components of dSC-mediated responses. Similarly, extracellular recordings from putative GiA sympathetic premotor neurons confirmed short-latency excitatory inputs from the dSC. This pathway represents a likely substrate for autonomic components of orienting responses that are mediated by dSC neurons and suggests a mechanism through which physiological and motor components of orienting behaviours may be integrated without the involvement of higher centres that mediate affective components of defensive responses. KEY POINTS: Neurons in the deep superior colliculus (dSC) integrate multimodal sensory signals to elicit context-dependent innate behaviours that are accompanied by stereotypical cardiovascular and respiratory activities. The pathways responsible for mediating the physiological components of colliculus-mediated orienting behaviours are unknown. We show that optogenetic dSC stimulation evokes transient orienting, respiratory and autonomic effects in awake rats which persist under urethane anaesthesia. Anterograde tracing from the dSC identified projections to spinally projecting neurons in the medullary gigantocellular reticular nucleus (GiA). Stimulation of this pathway recapitulated autonomic effects evoked by stimulation of dSC neurons. Electrophysiological recordings from putative GiA sympathetic premotor neurons confirmed short latency excitatory input from dSC neurons. This disynaptic dSC-GiA-spinal sympathoexcitatory pathway may underlie autonomic adjustments to salient environmental cues independent of input from higher centres.

The effect of self-administered methamphetamine on GABAergic interneuron populations and functional connectivity of the nucleus accumbens and prefrontal cortex.

INTRODUCTION: Methamphetamine (METH, "ice") is a potent and addictive psychostimulant. Abuse of METH perturbs neurotransmitter systems and induces neurotoxicity; however, the neurobiological mechanisms which underlie addiction to METH are not fully understood, limiting the efficacy of available treatments. Here we investigate METH-induced changes to neuronal nitric oxide synthase (nNOS), parvalbumin and calretinin-expressing GABAergic interneuron populations within the nucleus accumbens (NAc), prefrontal cortex (PFC) and orbitofrontal cortex (OFC). We hypothesise that dysfunction or loss of these GABAergic interneuron populations may disrupt the excitatory/inhibitory balance within the brain. METHODS: Male Long Evans rats (N = 32) were trained to lever press for intravenous METH or received yoked saline infusions. Following 14 days of behavioural extinction, animals were given a non-contingent injection of saline or METH (1 mg/kg, IP) to examine drug-primed reinstatement to METH-seeking behaviours. Ninety minutes post-IP injection, animals were culled and brain sections were analysed for Fos, nNOS, parvalbumin and calretinin immunoreactivity in eight distinct subregions of the NAc, PFC and OFC. RESULTS: METH exposure differentially affected GABAergic populations, with METH self-administration increasing nNOS immunoreactivity at distinct locations in the prelimbic cortex and decreasing parvalbumin immunoreactivity in the NAc. METH self-administration triggered reduced calretinin immunoreactivity, whilst acute METH administration produced a significant increase in calretinin immunoreactivity. As expected, non-contingent METH-priming treatment increased Fos immunoreactivity in subregions of the NAc and PFC. CONCLUSION: Here we report that METH exposure in this model may alter the function of GABAergic interneurons in more subtle ways, such as alterations in neuronal firing or synaptic connectivity.

Oxytocin as an adolescent treatment for methamphetamine addiction after early life stress in male and female rats.

Early life stress (ELS) is associated with perturbed neural development and augmented vulnerability to mental health disorders, including addiction. How ELS changes the brain to increase addiction risk is poorly understood, and there are no therapies which target this ELS-induced vulnerability. ELS disrupts the oxytocin system, which can modulate addiction susceptibility, suggesting that targeting the oxytocin system may be therapeutic in this ELS-addiction comorbidity. Therefore, we determined whether adolescent oxytocin treatment after ELS could: (1) reduce vulnerability to anxiety, social deficits, and methamphetamine-taking and reinstatement; and (2) restore hypothalamic oxytocin and corticotropin-releasing factor expressing neurons and peripheral oxytocin and corticosterone levels. Long Evans pups underwent maternal separation (MS) for either 15 min or 360 min on postnatal days (PND) 1-21. During adolescence (PNDs 28-42), rats received a daily injection of either oxytocin or saline. In Experiment 1, adult rats were assessed using the elevated plus-maze, social interaction procedure, and methamphetamine self-administration procedure, including extinction, and cue-, methamphetamine- and yohimbine-induced reinstatement. In Experiment 2, plasma for enzyme immunoassays and brain tissue for immunofluorescence were collected from adult rats after acute stress exposure. Adolescent oxytocin treatment ameliorated ELS-induced anxiety and reduced methamphetamine- and yohimbine-induced reinstatement in both sexes, and suppressed methamphetamine intake and facilitated extinction in males only. Additionally, adolescent oxytocin treatment after ELS restored oxytocin-immunoreactive cells and stress-induced oxytocin levels in males, and attenuated stress-induced corticosterone levels in both sexes. Adolescent oxytocin treatment reverses some of the ELS effects on later-life psychopathology and vulnerability to addiction.

Cannabidiol but not cannabidiolic acid reduces behavioural sensitisation to methamphetamine in rats, at pharmacologically effective doses.

RATIONALE: Cannabidiol (CBD) and cannabidiolic acid (CBDA) are non-psychoactive components of the cannabis plant. CBD has been well characterised to have anxiolytic and anticonvulsant activity, whereas the behavioural effects of CBDA are less clear. Preclinical and clinical data suggests that CBD has antipsychotic properties and reduces methamphetamine self-administration in rats. An animal model that is commonly used to mimic the neurochemical changes underlying psychosis and drug dependence is methamphetamine (METH) sensitisation, where repeated administration of the psychostimulant progressively increases the locomotor effects of METH. OBJECTIVE: The aim of this study was to determine whether CBD or CBDA attenuate METH-induced sensitisation of locomotor hyperactivity in rats. METHODS: Eighty-six male Sprague Dawley rats underwent METH sensitisation protocol where they were subjected to daily METH (1 mg/kg on days 2 and 8, 5 mg/kg on days 3-7; i.p.) injections for 7 days. After 21 days of withdrawal, rats were given a prior injection of CBD (0, 40 and 80 mg/kg; i.p.) or CBDA (0, 0.1, 10 and 1000 µg/kg; i.p.) and challenged with acute METH (1 mg/kg; i.p.). Locomotor activity was then measured for 60 min. RESULTS: Rats displayed robust METH sensitisation as evidenced by increased locomotor activity to METH challenge in METH-pretreated versus SAL-pretreated rats. CBD (40 and 80 mg/kg) reduced METH-induced sensitisation. There was no effect of any CBDA doses on METH sensitisation or acute METH-induced hyperactivity. CONCLUSION: These results demonstrate that CBD, but not CBDA, reduces METH sensitisation of locomotor activity in rats at pharmacologically effective doses, thus reinforcing evidence that CBD has anti-addiction and antipsychotic properties.

The effect of adolescent social isolation on vulnerability for methamphetamine addiction behaviours in female rats.

RATIONALE: Stress exposure during adolescence contributes to developing a methamphetamine (METH) use disorder. However, most of the studies investigating addiction-related behaviours include only male rodents, despite METH addiction rates being higher in females. Furthermore, animal studies investigating the effects of stress on methamphetamine addiction have used only basic self-administration models which may not be sensitive to the effects of stress. OBJECTIVES: This project explored whether adolescent isolation stress exposure increases the incidence of four key addiction-related behaviours in female rats. METHODS: Thirty-two female rat pups were caged in groups of four or individually during adolescence from postnatal (PND) day 22, with the latter being re-socialised in groups of four on PND 43. In adulthood, rats were tested for addiction-like behaviours in a METH self-administration paradigm modelling motivation to take METH, persistence in drug-seeking behaviour when METH was not available, resistance to extinction, and propensity to reinstate after a period of withdrawal. RESULTS: Adolescent social isolation resulted in lower METH intake during acquisition; however, the paradigm modelling drug-seeking when the drug was unavailable engendered intermittent METH bingeing in all rats, abolishing the group differences in intake during this phase. Adolescent social isolation also accelerated extinction of non-reinforced lever pressing, and increased stress-primed reinstatement, compared to the group-housed rats. CONCLUSIONS: Adolescent social isolation stress alters various methamphetamine addiction-like behaviours in female rats.

Sex Differences in Substance Use Disorders: A Neurobiological Perspective.

Clinical studies provide fundamental knowledge of substance use behaviors (substance of abuse, patterns of use, relapse rates). The combination of neuroimaging approaches reveal correlation between substance use disorder (SUD) and changes in neural structure, function, and neurotransmission. Here, we review these advances, placing special emphasis on sex specific findings from structural neuroimaging studies of those dependent on alcohol, nicotine, cannabis, psychostimulants, or opioids. Recent clinical studies in SUD analyzing sex differences reveal neurobiological changes that are differentially impacted in common reward processing regions such as the striatum, hippocampus, amygdala, insula, and corpus collosum. We reflect on the contribution of sex hormones, period of drug use and abstinence, and the potential impact of these factors on the interpretation of the reported findings. With the overall recognition that SUD impacts the brains of females and males differentially, it is of fundamental importance that future research is designed with sex as a variable of study in this field. Improved understanding of neurobiological changes in males and females in SUD will advance knowledge underlying sex-specific susceptibility and the neurobiological impact in these disorders. Together these findings will inform future treatments that are tailor designed for improved efficacy in females and males with SUD.

Adolescent oxytocin administration reduces depression-like behaviour induced by early life stress in adult male and female rats.

Early life stress (ELS) exposure alters brain development, increasing vulnerability for mental illness in adulthood, including depression. Despite this association, there are no approved pharmacotherapies to protect against the emergence of mental illness resulting from ELS. Recent preclinical work showed that oxytocin (OT) administration in adulthood reduced depressive-like behaviour in male rats with a history of ELS. However, the ability of an OT treatment regime in adolescence, a critical developmental window for the OT system, to prevent the expression of depressive-like behaviours following ELS has not been investigated. Therefore, the present study aimed to determine whether chronic OT administration can ameliorate the enduring effects of ELS on depressive-like behaviours in both male and female rats. Following birth, Long Evans rat pups (N = 107) underwent maternal separation (MS) for either 15 min (MS15) or 6 h (MS360) on postnatal days (PND) 1-21. During adolescence (PND 28-42), rats received a daily injection of either OT (1 mg/kg) or saline. During adulthood (PND 57 onwards), effort-related motivation was measured using a model of effortful choice (EC), while behavioural despair was measured using the forced swim test (FST). Lastly, body and organ weights were measured to examine the physiological impacts of ELS and chronic OT administration. Overall, in both sexes, MS360 increased behavioural despair yet had no impact on effort-related motivation. Importantly, adolescent OT administration prevented the MS360-induced increase in behavioural despair in both males and females. Additionally, MS360 resulted in persistent reductions in body weight in both sexes post-weaning and increased spleen weight in males and adrenal weight in females. OT treatment had no impact on body weight in either sex, but prevented the MS-induced increase in adrenal gland weight in females. Overall, these findings have important implications for using oxytocin as a preventative pharmacotherapy after ELS.

The vagus nerve mediates the suppressing effects of peripherally administered oxytocin on methamphetamine self-administration and seeking in rats.

The neuropeptide oxytocin has emerged as a promising pharmacotherapy for methamphetamine (METH) addiction, and clinical trials of intranasal oxytocin are underway. However, there is debate as to how peripherally administered oxytocin alters brain signalling to modulate addiction processes. Interestingly, there is evidence for functional interactions between peripheral oxytocin administration and the vagus nerve. Therefore, this study investigated whether the effects of peripherally administered oxytocin require vagal signalling to reduce METH self-administration and reinstatement of METH-seeking behaviours. Male and female Sprague-Dawley rats underwent surgery for jugular catheterisation and either subdiaphragmatic vagotomy (SDV) or a sham operation. Rats were trained to self-administer METH, and the effect of peripherally administered oxytocin on METH intake was assessed. Rats then underwent extinction, and effects of oxytocin were assessed on cue- and METH-induced reinstatement of METH-seeking. Oxytocin treatment robustly attenuated METH intake in both sexes, and SDV entirely prevented the suppressant effect of oxytocin (0.3 mg/kg) on METH intake, and partially prevented the effects of 1 mg/kg oxytocin in both sexes. After extinction, SDV decreased the suppressing effects of oxytocin on cue- and METH-primed reinstatement in males, but not females. SDV was functionally confirmed by measuring food intake following administration of the vagal dependent peptide, cholecyostokin-8. Our data suggest that vagus nerve signalling is required for the inhibitory effects of peripherally administered oxytocin on METH self-administration and reinstatement, and that this vagal dependency is partially mediated by sex and drug withdrawal. This study has implications for the use of oxytocin as a therapy for METH use disorder for both sexes.

Sign tracking predicts cue-induced but not drug-primed reinstatement to methamphetamine seeking in rats: Effects of oxytocin treatment.

BACKGROUND: The incentive sensitisation theory of addiction posits that drug-associated stimuli become imbued with incentive motivational properties, driving pathological drug seeking. However, pre-existing variability in the incentive salience to non-drug reward cues ('sign trackers' (STs); 'goal trackers' (GTs)) is also predictive of the desire for and relapse to cocaine and opioids. Here, we asked whether variation in propensity to attribute incentive salience to a food cue is predictive of reinstatement to the highly addictive psychostimulant methamphetamine (METH), and whether treatment with the promising anti-addiction therapy oxytocin differentially reduces METH behaviour between STs and GTs. METHODS: Rats were trained to associate a Pavlovian cue with delivery of a sucrose pellet over 8 days. They then received jugular vein catheters for intravenous METH self-administration, followed by behavioural extinction, and cue-induced and METH-primed reinstatement to METH-seeking behaviours. Oxytocin was administered prior to self-administration and reinstatement tests. RESULTS: Despite the self-administration of similar amounts of METH, STs reinstated more to METH cues than did GTs, yet METH-priming reinstated STs and GTs similarly. Furthermore, oxytocin attenuated cue-induced reinstatement more so in STs than in GTs, and reduced METH-primed reinstatement to a greater extent in the top quartile of reinstaters, indicating that oxytocin treatment may be most effective for those at highest risk of addiction. CONCLUSIONS: This pre-existing bias towards reward cues presents a possible tool to screen for METH addiction susceptibility and may be useful for understanding the neurobiology of addiction and for pharmacotherapeutic discovery.

Differential effects of GABAA receptor activation in the prelimbic and orbitofrontal cortices on anxiety.

RATIONALE: The development of effective anxiety treatments has been hindered by limited understanding of the neurobiological mechanisms involved in anxiety regulation. Whilst gamma-aminobutyric acid (GABA) neurotransmission in the prefrontal cortex (PFC) is one mechanism consistently implicated in anxiety regulation, PFC subregions may contribute uniquely. OBJECTIVES: The present study examined the effects of inactivating the PFC subregions of the prelimbic cortex (PrL) or orbitofrontal cortex (OFC) through GABAA receptor (GABAAR) activation, on anxiety behaviours in male Wistar rats. METHODS: Sixty-six male Wistar rats were surgically implanted with bilateral cannulae into the PrL (n = 33) or the OFC (n = 33). Rats then received a microinjection of either the GABAA receptor agonist muscimol or vehicle prior to each experiment, conducted 1 week apart. Measures of anxiety were examined using the elevated plus maze (EPM) and the emergence test (ET). The effect on locomotor activity (baseline or methamphetamine-induced) was also tested. RESULTS: Differential effects of brain region inactivation on anxiety-like behaviour were shown by measures in the EPM and ET; muscimol infused into the PrL-reduced anxiety-like behaviour, yet had no significant effect when infused into the OFC, compared with control treated rats. No effects on locomotor activity at baseline or following methamphetamine treatment were found. CONCLUSIONS: This study highlights that activation of GABAARs specifically within the PrL, but not OFC, reduces anxiety behaviours in male rats. This suggests that activity of the PrL plays a more important role than the OFC in the neurobiological mechanisms of unconditioned anxiety and should be targeted for future therapies.

Maternal separation changes maternal care, anxiety-like behaviour and expression of paraventricular oxytocin and corticotrophin-releasing factor immunoreactivity in lactating rats.

The early postnatal period is a time of tremendous change for the dam and her offspring. During this time, environmental insults such as repeated stress exposure can have detrimental effects. In research that has focused on the effect of postnatal stress exposure on the dams, conflicting changes in maternal care and anxiety-like behaviour have been reported. Additionally, changes to hypothalamic neuropeptides that are crucially involved in the transition to motherhood and stress regulation, namely oxytocin and corticotrophin-releasing factor (CRF), have not been examined. Accordingly, the present study aimed to determine (i) whether repeated postpartum stress increases engagement in maternal care behaviours and anxiety-like behaviour and (ii) whether these behavioural changes correspond with changes to CRF- or oxytocin-immunoreactive (-IR) cells in the paraventricular nucleus (PVN) of the hypothalamus. A non-lactating group was also included to control for the effects of lactation on anxiety and the hypothalamic neuroendocrine system. Following the birth of their litters, Long-Evans dams were separated from their pups from postnatal day (PND) 1 to PND21 for either 15 minutes (maternal separation [MS]15) or 6 hours (MS360). Maternal behaviours were recorded for 30 minutes on select PNDs following the separation. On PND22, dams were exposed to the elevated plus maze, brains were collected, and immunofluorescence analysis of PVN oxytocin- and CRF-IR cells was conducted. Our findings demonstrate that prolonged maternal separation altered typical maternal behaviours and reduced anxiety relative to MS15 dams. At the cellular level, oxytocin-IR cells in the caudal PVN were reduced in MS360 dams to a level similar to that in non-lactating controls, and PVN CRF-IR cells were reduced relative to both MS15 and non-lactating controls. Taken together, these data reveal the behavioural and neuronal changes that occur in the mother dam following repeated postnatal stress exposure.

The impact of early life stress on the central oxytocin system and susceptibility for drug addiction: Applicability of oxytocin as a pharmacotherapy.

Early life trauma is strongly associated with an increased vulnerability to abuse illicit drugs and the impairment of neural development. This includes alterations to the development of the oxytocin system, which plays a pivotal role in the regulation of social behaviours and emotion. Dysregulation of this important system also contributes to increased susceptibility to develop drug addiction. In this review, we provide an overview of the animal models of early life stress that are widely used, and discuss the impact that early life stress has on drug-taking behaviour in adolescence and adulthood in both sexes. We link this to the changes that early life stress has on the endogenous oxytocin system, and how exogenously administered oxytocin may help to re-establish functioning of the system, and in turn, reduce drug-taking behaviour.

The effect of chronic oxytocin treatment during abstinence from methamphetamine self-administration on incubation of craving, reinstatement, and anxiety.

Methamphetamine (METH) abuse is characterised by chronic relapse and anxiety, for which there are no effective pharmacotherapies. Acute treatment with the neuropeptide oxytocin has shown therapeutic potential for METH addiction and has social and anxiolytic effects in METH-naïve rats. However, the effects of chronic oxytocin treatment in METH-experienced rats are unknown. This study investigated the effects of repeated oxytocin treatment during abstinence from METH self-administration on incubation of cue-induced relapse, yohimbine- and METH-induced reinstatement, trait anxiety, and social interaction. Male and female Sprague-Dawley rats self-administered intravenous METH for 2 h/day (12 days) and then on short-access (2 h/day; ShA) or long-access (6 h/day; LgA) sessions (10 days). Rats underwent 30 days of drug abstinence, during which they received 15 days of intraperitoneal oxytocin (1 mg/kg) or saline (days 6-20) injections. Anxiety and social interaction were tested on days 25-28, and incubation was assessed by testing cue-induced relapse on days 2 and 30. Rats underwent extinction after the final cue-relapse test, followed by yohimbine- and METH-primed reinstatement. LgA, but not ShA rats exhibited incubation of METH-craving and enhanced METH-primed reinstatement in both sexes, and enhanced yohimbine-induced reinstatement in females. Importantly, chronic oxytocin attenuated incubation and METH-primed reinstatement in both sexes, and yohimbine-induced reinstatement in females, although only in LgA rats. LgA produced a heightened anxiety phenotype, which was partially rescued by chronic oxytocin treatment. Using a translatable addiction model, these findings demonstrate the therapeutic efficacy of chronic oxytocin after METH self-administration and supports the clinical utility of oxytocin for METH addiction in both sexes.

Inhibitory regulation of the prefrontal cortex following behavioral sensitization to amphetamine and/or methamphetamine psychostimulants: A review of GABAergic mechanisms.

Behavioral sensitization to repeated psychostimulant administration has been proposed to reflect many of the neurochemical and behavioral changes that are characteristic of a range of disorders, including drug addiction and psychoses. While previous studies have examined the role of dopamine and glutamate neurotransmission in mediating sensitization, particularly within the prefrontal cortex (PFC), the role of inhibitory GABAergic processing of the PFC in the expression of sensitization is not well understood. Recent research, however, has proposed an emerging role of GABA synthesis, reuptake, ionotropic and metabotropic receptor regulation, and interneuronal changes following sensitization to methamphetamine and/or amphetamine within the PFC. The aim of this review, therefore, is to synthesize research findings on changes to the GABAergic network following sensitization induced by amphetamines (i.e., amphetamine and/or methamphetamine) in the PFC. In addition to providing an overview of global PFC changes, we also provide evidence of regional specific inhibitory influences on sensitized circuitry, focusing on the prelimbic and orbitofrontal cortices. We propose a neural circuit through which inhibitory PFC GABA changes mediate sensitized disease states, focusing on the interaction between the prelimbic and orbitofrontal cortices with subcortical brain structures and the mesolimbic system. Methodological considerations and avenues for future research are also discussed.

A Comparison of Methamphetamine-Induced Psychosis and Schizophrenia: A Review of Positive, Negative, and Cognitive Symptomatology.

Methamphetamine is a potent psychostimulant that can induce psychosis among recreational and chronic users, with some users developing a persistent psychotic syndrome that shows similarities to schizophrenia. This review provides a comprehensive critique of research that has directly compared schizophrenia with acute and chronic METH psychosis, with particular focus on psychiatric and neurocognitive symptomatology. We conclude that while there is considerable overlap in the behavioral and cognitive symptoms between METH psychosis and schizophrenia, there appears to be some evidence that suggests there are divergent aspects to each condition, particularly with acute METH psychosis. Schizophrenia appears to be associated with pronounced thought disorder, negative symptoms more generally and cognitive deficits mediated by the parietal cortex, such as difficulties with selective visual attention, while visual and tactile hallucinations appear to be more prevalent in acute METH-induced psychosis. As such, acute METH psychosis may represent a distinct psychotic disorder to schizophrenia and could be clinically distinguished from a primary psychotic disorder based on the aforementioned behavioral and cognitive sequelae. Preliminary evidence, on the other hand, suggests that chronic METH psychosis may be clinically similar to that of primary psychotic disorders, particularly with respect to positive and cognitive symptomatology, although negative symptoms appear to be more pronounced in schizophrenia. Limitations of the literature and avenues for future research are also discussed.

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

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

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

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