Centre for Youth Mental Health - Research Publications
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ItemExtinction of a cocaine-taking context that protects against drug-primed reinstatement is dependent on the metabotropic glutamate 5 receptor(WILEY, 2015-05)We investigated the effects of extinguishing action-reward versus context-reward associations on drug-primed reinstatement, and the potential role of the metabotropic glutamate 5 receptor (mGlu5) in these different types of extinction in rats that self-administer cocaine. We observed that daily context extinction (non-reinforced exposures to the cocaine-taking context with retracted levers) was just as effective as daily lever extinction in reducing cocaine-primed reinstatement compared with passive abstinence. Additionally, systemic injections of the mGlu5 negative allosteric modulator MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine) following each extinction session significantly impaired the ability of context extinction to reduce cocaine-primed reinstatement, without affecting reinstatement after lever extinction or passive abstinence.
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ItemMGLU5 receptors are necessary for extinction of drug associated cues and contexts(Wiley, 2017-08-01)Drug-associated cues and contexts are strong predictors of relapse. We used complex behavioural preparations to examine whether extinction of such cues reduces their capacity to trigger drug-seeking. We also examined whether the mGlu5 receptor is necessary for extinction learning. In Experiment 1, rats were trained to lever press for cocaine. Once stable responding was established, the context was extinguished by replacing the rats in the chambers, but with no opportunity to respond (levers were retracted). Control group remained in their home cage. An mGlu5 receptor negative allosteric modulator (MTEP) or vehicle was administered immediately after context extinction sessions. During subsequent drug-induced reinstatement, rats responded less if they had received context extinction; however, this effect was attenuated where MTEP had been applied. In Experiment 2, rats were trained to lever press for cocaine, now paired with a cue light. To extinguish the cue, half of the rats were placed in the chambers and given non-reinforced presentations of the cue, but with the levers retracted. Control rats remained in home cage. All rats received either MTEP or vehicle 20 minutes prior. Cue-induced reinstatement was tested the following day by re-pairing the lever with the light. Rats gave fewer drug-seeking responses following cue extinction. This effect was attenuated by MTEP. Experiment 3 followed the same protocol as Experiment 2, except that a positive allosteric modulator CDPPB or vehicle was administered 20 minutes before CS extinction. At reinstatement, cue-elicited cocaine seeking was lower for the animals that had previously been administered CDPPB, regardless of extinction condition. This study highlights the important role cues and contexts play in driving drug-seeking behaviour during reinstatement. It also shows that mGlu 5 signalling is necessary for extinction of drug-cue associations, and that mGlu5 positive allosteric modulators are promising targets for treating cocaine addiction.
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ItemPrefrontal Dopaminergic Mechanisms of Extinction in Adolescence Compared to Adulthood in Rats(FRONTIERS MEDIA SA, 2017-02-22)Adolescents with anxiety disorders attain poorer outcomes following extinction-based treatment compared to adults. Extinction deficit during adolescence has been identified to involve immaturity in the medial prefrontal cortex (mPFC). Findings from adult rodents suggest extinction involves dopamine signaling in the mPFC. This system changes dramatically during adolescence, but its role in adolescent extinction is unknown. Therefore, we investigated the role of prefrontal dopamine in extinction using Pavlovian fear conditioning in adolescent and adult rats. Using quantitative PCR (qPCR) analyses, we measured changes in dopamine receptor gene expression in the mPFC before and after extinction. We then enhanced dopamine 1 receptor (D1R) or dopamine 2 receptor (D2R) signaling in the infralimbic cortex (IL) of the mPFC using agonists at the time of extinction. Adolescent rats displayed a deficit in extinction retention compared to adults. Extinction induced a reduction in D1R compared to D2R gene expression in adolescent rats, whereas an increase of D1R compared to D2R gene expression was observed in adult rats. Acutely enhancing IL D1R signaling using SKF-81297 had no effect on extinction at either age. In contrast, acutely enhancing IL D2R signaling with quinpirole significantly enhanced long-term extinction in adolescents, and impaired within-session extinction in adults. Our results suggest a dissociated role for prefrontal dopamine in fear extinction during adolescence compared to adulthood. Findings highlight the dopamine system as a potential pharmacological target to improve extinction-based treatments for adolescents.
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ItemAripiprazole Facilitates Extinction of Conditioned Fear in Adolescent Rats(FRONTIERS MEDIA SA, 2017-05-09)Anxiety disorders are the most common type of mental disorder during adolescence, which is at least partly due to the resistance to extinction exhibited at this age. The dopaminergic system is known to be dysregulated during adolescence; therefore, we aimed to facilitate extinction in adolescent rats using the dopamine receptor 2 partial agonist aripiprazole (Abilify™), and examine the behavioral and neural outcomes. Adolescent rats were conditioned to fear a tone. The next day, rats received extinction 30 min after a systemic injection of either 5 mg/kg aripiprazole or vehicle, and then were tested the following day. For the immunohistochemistry experiment, naïve and "no extinction" conditions were added and rats were perfused either on the extinction day or test day. To assess the activation of neurons receiving dopaminergic input, c-Fos, and dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32) labeled neurons were quantified in the amygdala and the medial prefrontal cortex (mPFC). Systemic treatment with aripiprazole at the time of extinction significantly reduced freezing at test the next day. This effect was not observed in rats that were fear conditioned but did not receive any extinction. Aripiprazole's facilitation of extinction was accompanied by increased activation of neurons in the mPFC. Taken together, aripiprazole represents a novel pharmacological adjunct to exposure therapy worthy of further examination. The effect of aripiprazole is related to enhanced activation of mPFC neurons receiving dopaminergic innervation.
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ItemCognition and Related Neural Findings on Methamphetamine Use Disorder: Insights and Treatment Implications From Schizophrenia Research(FRONTIERS MEDIA SA, 2019-12-17)Despite the prevalence of methamphetamine (meth) use disorder, research on meth is disproportionately scarce compared to research on other illicit drugs. Existing evidence highlights cognitive deficits as an impediment against daily function and treatment of chronic meth use. Similar deficits are also observed in schizophrenia, and this review therefore draws on schizophrenia research by examining similarities and differences between the two disorders on cognition and related neural findings. While meth use disorder and schizophrenia are two distinct disorders, they are highly co-morbid and share impairments in similar cognitive domains and altered brain structure/function. This narrative review specifically identifies overlapping features such as deficits in learning and memory, social cognition, working memory and inhibitory/impulse control. We report that while working memory deficits are a core feature of schizophrenia, such deficits are inconsistently observed following chronic meth use. Similar structural and functional abnormalities are also observed in cortical and limbic regions between the two disorders, except for cingulate activity where differences are observed. There is growing evidence that targeting cognitive symptoms may improve functional outcome in schizophrenia, with evidence of normalized abnormal brain activity in regions associated with cognition. Considering the overlap between meth use disorder and schizophrenia, targeting cognitive symptoms in people with meth use disorder may also improve treatment outcome and daily function.