We previously found that intermittent administration of 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) to adolescent male rats protected against the behavioral and serotonergic neurotoxic effects of a subsequent MDMA binge. Similar results have been reported for the dopamine (DA) neurotoxin methamphetamine (METH). The present study tested the hypothesis that intermittent adolescent MDMA exposure would protect against the DA neurotoxic effects of a METH binge. Male Sprague-Dawley rats were injected s.c. with MDMA (10 mg/kg x 2; 4-h interdose interval) or saline every fifth day from postnatal day (PD) 35 through PD 60. The animals were then challenged with either a low- or high-dose METH binge (4 or 8 mg/kg x 4; 2- h interdose interval) or saline on PD 67. Activity was measured 1 day after the binge, and regional serotonin transporter (SERT) and dopamine transporter (DAT) expression were analyzed at PD 74 by radioligand binding. All animals treated with METH on the challenge day became hyperthermic, independent of pretreatment conditions. Both MDMA-pretreated and drug-naïve rats also showed a dose-dependent hypoactivity 24 h after the first dose of the METH binge. The SERT binding results indicated that adolescent pretreatment with MDMA provided full or partial protection (depending on the brain region) against the serotonergic deficits produced by METH in previously drug-naïve animals. In contrast, MDMA pretreatment failed to protect against METH-induced decreases in striatal DAT binding. These results suggest that the neuroprotective 2 effects of adolescent MDMA pretreatment are confined to the serotonergic system, possibly reflecting a selective upregulation of antioxidant mechanisms in that system.

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The hypocretin/orexin (HCRT) system is associated with compulsive stimulant drug use, involving both HCRT-receptor 1 (-R1) and HCRT-receptor 2 (-R2). Few studies, however, have examined the role of HCRT-R2 or combined HCRT-R1/2 on compulsive methamphetamine (METH) taking behavior. In this study, we examined the effects of HCRT-R1, -R2, and -R1/2 antagonists on compulsive METH self-administration, as modeled by escalated intake in adult male Wistar rats allowed extended access to METH. Three cohorts of rats were allowed either short (1h; ShA; n=7-10/cohort) or long (6h; LgA; n=7-9/cohort) access to METH intravenous self-administration for 14 sessions (fixed ratio 1 schedule). Each cohort was then systemically administered a single- or dual-HCRT-R antagonist 30 min prior to METH self-administration testing: cohort 1, selective HCRT-R1 antagonist (RTIOX-276; RTI-R1; 0, 10, and 20 mg/kg); cohort 2, selective HCRT-R2 antagonist (JNJ-10397049; JNJ-R2; 0, 10, and 20 mg/kg); and cohort 3, dual HCRT-R1/2 antagonist (Suvorexant; SUV-R1/2; 0, 30, and 60 mg/kg). RTI-R1 elicited a dose-dependent reduction in METH intake in LgA, but not ShA, in the first hour. Administration of JNJ-R2 had no effect on METH intake in the first hour in neither ShA nor LgA rats, but reduced METH intake during the full 6 h session at the lowest dose. SUV-R1/2 administration had no effect on METH intake in ShA rats, but showed significant attenuation of METH-taking at the highest dose in both the first hour and full 6h session for LgA rats. Locomotor activity was significantly reduced following RTI-R1 and SUV-R1/2 in ShA rats only. To further explore the role that HCRT plays in METH dependence after a period of abstinence, we used a shRNA-encoding adeno-associated viral vector (AAV) to silence Hcrt in a separate cohort of previously-escalated METH-dependent rats. Following an initial escalation phase, and prior to a 3-week period of drug abstinence, rats were injected with either a control scramble-RNA AAV (AAV-Scram; n= 4) or a Hcrt-knockdown AAV (AAV-HCRT-KD; n= 5). AAV-Scram rats showed a significant decrease in METH self-administration post-abstinence, and a subsequent increase in METH-taking following a re-escalation period. In contrast, AAV-HCRT-KD rats showed a significant attenuation of METH self-administration following the re-escalation period. Combined, these results suggest HCRT neurotransmission at both HCRT-R1 and -R2 may contribute to compulsive METH-taking behavior.

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Introduction – Dissocié un trouble psychiatrique primaire (TPP) concomitant à un problème d’abus de substances d’une psychose induite par consommation de substance (PICS) peut être une tâche difficile puisque plusieurs symptômes sont similaires. La dichotomie entre les symptômes négatifs et les symptômes positifs de la schizophrénie a été suggéré comme étant un indicateur puisque les symptômes négatifs ne sont pas caractéristiques d’un double diagnostic (Potvin, Sepehry, & Stip, 2006). Objectif – Cette étude explore la possibilité de distinguer des sous-groupes au sein de notre échantillon en utilisant le fonctionnement cognitif en vue d’identifier des facteurs qui permettraient un meilleur défférentiel entre un TPP concomitant à un problème d’abus de substance d’une psychose induite par consommation de méthamphétamines (MA). L’hypothèse stipule que les individus avec un TPP présenteraient des déficits cognitifs différents comparativement aux individus avec une PICS. Méthode – Les données utilisés font parties d’une étude longitudinale qui s’est déroulée à Vancouver, CB, Canada. 172 utilsateurs de MA et présentant une psychose ont été recruté. L’utilisation de substances, la sévérité des symptômes et des déficits cognitifs ont été évalué. Résultats – Des analyses par regroupement ont révélé deux profiles: les individus du Groupe 1 ont une performance inférieure au score total du Gambling task (M=-28,1) ainsi qu’un pourcentage de rétention inférieur au Hopkins Verbal Learning Test – Revised (HVLT- R; M=63) comparativement à ceux du Groupe 2. Les individus du Groupe 1 ont plus de symptômes négatifs, t=2,29, p<0.05 et ont plus tendance à avoir reçu un diagnostic psychiatrique, X2(3) = 16.26, p< 0.001. Conclusion – Les résultats suggèrent que des facteurs cognitifs pourraient aider à identifier un TPP concomitant à l’abus de MA. / Introduction - Dissociating a primary psychotic disorder (PPD) with concurrent substance use from substance-induced psychosis (SIP) can be a difficult task since several symptoms are similar. The dichotomy between negative and positive symptoms in schizophrenia has been hypothesized as a predictor, as the former is not typically a feature of a dual disorder (Potvin, Sepehry, & Stip, 2006). Objective - This study explored the possibility of distinguishing subgroups within our sample using cognitive functioning to further identify factors that could help the differential diagnosis between a PPD co-occurring with substance-use and a methamphetamine (MA) induced psychosis. The hypothesis stipulates that individuals with a PPD should present with different cognitive deficits compared to individuals with SIP. Methods - This study used the data collected as part of a longitudinal study (the MAPS project) that took place in Vancouver BC, Canada. 172 individuals presenting with psychosis and MA abuse were recruited. Substance use, symptoms severity and cognitive deficits were assessed. Results - Cluster analyses revealed two profiles: individuals in Cluster 1 had a poorer performance on the Gambling task net score (M=-28,1) as well as on the Hopkins Verbal Learning Test - Revised (HVLT-R; M=63) % of retention score compared to those in Cluster 2. Individuals in Cluster 1 also had more negative symptoms than individuals in Cluster 2, t=2,29, p<0.05 and were more likely to have had a psychiatric diagnosis, X2(3) = 16.26, p< 0.001. Conclusion - Results suggest that cognitive predictors might help identify PPD that co-occur with MA abuse.

Methamphetamine is a psychomotor stimulant that produces hyperactivity and euphoria and can lead to drug-seeking and abuse. An estimate from 2005 put the cost of methamphetamine abuse to society at an estimated 23.4 billion dollars. One of methamphetamine's effects is activation of glial cells and associated neuroinflammatory activity in the periphery and CNS. Glia are responsible for maintaining calcium homeostasis, neuroplasticity, immune activity, and cell signaling. Activation of glia and neuroinflammation are becoming recognized as links in drug abuse-related behavior. The goal of the present work was to assess the ability of ibudilast, AV1013, and minocycline, three glial cell modulating compounds, to attenuate responding in rodent procedures that model different aspects of methamphetamine abuse-related behavior. First, Ibudilast (1.8, 7.5, 13 mg/kg) and AV1013 (10, 30, 56 mg/kg) were examined for their effects on methamphetamine-induced (3 mg/kg) locomotor activity and sensitization in mice, the latter thought to involve neurocircuitry common with drug relapse. Ibudilast and AV1013 dose-dependently attenuated methamphetamine-induced locomotor activity and its sensitization. Second, ibudilast (1, 7.5, 10 mg/kg), AV1013 (1, 10, 30 mg/kg), and minocycline (10, 30, 60 mg/kg) were examined for their effects on methamphetamine self-administration (0.001, 0.03, and 0.1 mg/kg/inf) in rats. All three compounds significantly reduced methamphetamine (0.03 mg/kg/inf) self-administration. Results suggested baseline self-administration rate as a possible determinant of these effects; however, follow-up tests with ibudilast while controlling for baseline response rate dismissed this possibility. Additional follow-up tests identified whether the attenuation of operant response rates was specific to methamphetamine-maintained behavior. Using a behavioral economic approach, all three test compounds were determined to also affect non-nutritive banana pellet-maintained responding when the baseline strengths maintained by methamphetamine and banana pellet delivery were matched. Finally, ibudilast was evaluated for its effects on methamphetamine discrimination in rats, a procedure thought to model clinical subjective effects. Ibudilast (1, 7.5, 10 mg/kg) did not significantly modify methamphetamine’s discriminative stimulus effects when trained at either 1 or 0.56 mg/kg. These results support the hypothesis that attenuation of glial cell activity and neuroinflammation may be linked to some abuse-related behaviors of methamphetamine, reinforcing their examination as novel targets for treating methamphetamine abuse.

Charles University in Prague First Faculty of Medicine Study programme: Specialization in Health Care Branch of Study: Addictology PharmDr. Bc. Zbyněk Oktábec, Ph.D. et Ph.D. Design of Pilot Clinical Trial of Treatment of Hepatitis C in Polyvalent Problem Drug Users with Pharmacological Substitution of Opioids and Methamphetamine (HCV-PPDUSOM) Master's Thesis Advisor: Mgr. Roman Gabrhelík, Ph.D. Prague, 2016 Abstract Hepatitis C is one of the most serious blood-borne complications of somatic health status of drug users. The HCV-positive injecting drug users are therefore directly indicated for the treatment of this type (and other types also) of hepatitis. Problematic adherence and treatment compliance is obvious in this group. Both foreign and domestic experiences show that stabilization of the use of illegal (and/or illegally acquired) substances is the essential part of the treatment of hepatitis. The interaction of the high quality treatment of somatic, psychosocial and add-on pharmacological care, including the substitution of illegal (and/or illegally acquired) drugs, leads to patient's increased compliance and adherence to HCV treatment. This diploma thesis is presenting both the theoretical frame and the study design of the pilot clinical trial of HCV treatment with the supportive substitution...

Drug abuse as well as risky sexual behaviours has been identified, globally as well as in South Africa, as social problems with dire consequences. Research suggests that crystal methamphetamine use leads to risky sexual behaviours such having unprotected sex, which can lead to unplanned pregnancies, and sexually transmitted infections (STI's) including HIV infection. Adolescents as well as females have been identified as risk populations for both sexual risk behaviours and drug abuse. Furthermore, the Western Cape showed high rates of crystal methamphetamine addiction, especially in the under 20 age category, and the highest increase in the incidence of HIV infections in South Africa. This may be indicative of the magnitude of the problem of risky sexual behaviours in the context of crystal methamphetamine use in the Western Cape.