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Foll B.L.,Translational Addiction Research Laboratory | Foll B.L.,Center for Addiction and Mental Health | Foll B.L.,University of Toronto | Ng E.,Sinai University | And 2 more authors.
Current Topics in Behavioral Neurosciences | Year: 2015

Epidemiological studies indicate a high prevalence of tobacco smoking in subjects with psychiatric disorders. Notably, there is a high prevalence of smoking among those with dependence to other substances, schizophrenia, mood, or anxiety disorders. It has been difficult to understand how these phenomena interact with clinical populations as it is unclear what preceded what in most of the studies. These comorbidities may be best understood by using experimental approaches in well-controlled conditions. Notably, animal models represent advantageous approaches as the parameters under study can be controlled perfectly. This review will focus on evidence collected so far exploring how behavioral effects of nicotine are modified in animal models of psychiatric conditions. Notably, we will focus on behavioral responses induced by nicotine that are relevant for its addictive potential. Despite the clinical relevance and frequency of the comorbidity between psychiatric issues and tobacco smoking, very few studies have been done to explore this issue in animals. The available data suggest that the behavioral and reinforcing effects of nicotine are enhanced in animal models of these comorbidi-ties, although much more experimental work would be required to provide certainty in this domain. © Springer International Publishing Switzerland 2015


Gamaleddin I.,Translational Addiction Research Laboratory | Wertheim C.,U.S. National Institute on Drug Abuse | Zhu A.Z.X.,Translational Addiction Research Laboratory | Coen K.M.,Translational Addiction Research Laboratory | And 6 more authors.
Addiction Biology | Year: 2012

The cannabinoid system appears to play a critical facilitative role in mediating the reinforcing effects of nicotine and relapse to nicotine-seeking behaviour in abstinent subjects based on the actions of cannabinoid (CB) receptor antagonists. However, the effects of CB receptor stimulation on nicotine self-administration and reinstatement have not been systematically studied. Here, we studied the effects of WIN 55,212-2, a CB1/2 agonist, on intravenous nicotine self-administration under fixed-ratio (FR) and progressive-ratio (PR) schedules of reinforcement in rats. The effects of WIN 55,212-2 on responding for food under similar schedules were also studied. In addition, the effects of WIN 55,212-2 on nicotine- and cue-induced reinstatement of nicotine seeking were also studied, as well as the effects of WIN 55,212-2 on nicotine discrimination. WIN 55,212-2 decreased nicotine self-administration under the FR schedule. However, co-administration of WIN 55,212-2 with nicotine decreased responding for food, which suggests that this effect was non-selective. In contrast, WIN 55,212-2 increased both nicotine self-administration and responding for food under the PR schedule, produced dose-dependent reinstatement of nicotine seeking, and enhanced the reinstatement effects of nicotine-associated cues. Some of these effects were reversed by the CB1 antagonist rimonabant, but not by the CB2 antagonist AM630. In the drug discrimination tests between saline and 0.4 mg/kg nicotine, WIN 55,212-2 produced no nicotine-like discriminative effects but significantly potentiated discriminative stimulus effects of nicotine at the low dose through a CB1-receptor-dependent mechanism. These findings indicate that cannabinoid CB1-receptor stimulation increases the reinforcing effects of nicotine and precipitates relapse to nicotine-seeking behaviour in abstinent subjects. Thus, modulating CB1-receptor signalling might have therapeutic value for treating nicotine dependence. © 2011 The Authors, Addiction Biology © 2011 Society for the Study of Addiction.


Gamaleddin I.,Translational Addiction Research Laboratory | Gamaleddin I.,Center for Addiction and Mental Health | Zvonok A.,Northeastern University | Makriyannis A.,Northeastern University | And 4 more authors.
PLoS ONE | Year: 2012

Over the last decade there have been significant advances in the discovery and understanding of the cannabinoid system along with the development of pharmacologic tools that modulate its function. Characterization of the crosstalk between nicotine addiction and the cannabinoid system may have significant implications on our understanding of the neurobiological mechanisms underlying nicotine dependence. Two types of cannabinoid receptors (CB1 and CB2) have been identified. CB1 receptors are expressed in the brain and modulate drug taking and drug seeking for various drugs of abuse, including nicotine. CB2 receptors have been recently identified in the brain and have been proposed to play a functional role in mental disorders and drug addiction. Our objective was to explore the role of CB2 receptors on intravenous nicotine self administration under two schedules of reinforcement (fixed and progressive ratio) and on nicotine seeking induced by nicotine priming or by nicotine associated cues. For this, we evaluated the effects of various doses of the selective CB2 antagonist AM630 (1.25 to 5 mg/kg) and CB2 agonist AM1241 (1 to 10 mg/kg) on these behavioral responses in rats. Different groups of male Long Evans rats were trained to lever press for nicotine at a unit dose of 30 μg/kg/infusion. Subsequently, animals were randomized using a Latin-square design and injected with either AM1241 or AM630 using a counterbalanced within subject design. Administration of the CB2 ligands did not affect either nicotine-taking nicotine-seeking behavior. Our results do not support the involvement of CB2 receptors in nicotine-taking or nicotine-seeking behavior.


Le Strat Y.,Translational Addiction Research Laboratory | Le Strat Y.,Center for Addiction and Mental Health | Le Strat Y.,French Institute of Health and Medical Research | Le Strat Y.,Louis Mourier Hospital | And 6 more authors.
Journal of Affective Disorders | Year: 2011

Background: Little is known about the prevalence and comorbidity of Major Depressive Episode (MDE) during pregnancy in the general population. This study presents nationally representative data on the prevalence, correlates, and psychiatric comorbidities of depression in women during pregnancy and postpartum in the United States. Method: Data were drawn from the 2001-2002 National Epidemiological Survey on Alcohol and Related Conditions (NESARC). The NESARC is a survey of 43,093 adults aged 18 years and older residing in households in the United States of whom 14,549 were women 18 to 50 years old with known past-year pregnancy status. Diagnoses of depression and other mood, anxiety, and drug disorders were based on the Alcohol Use Disorder and Associated Disabilities Interview Schedule - DSM-IV version. Results: The overall prevalence of MDE during pregnancy was 12.4%. Among pregnant and postpartum women, depression was associated with younger age, ethnicity other than Latino, being widowed, divorced, separated or never married, traumatic events within the past 12 months and pregnancy complication. Strong associations were found between MDE during pregnancy and postpartum and nearly all 12-month psychiatric disorders. Past-year depressed pregnant and postpartum women were more likely than nondepressed pregnant women to use substances (including alcohol, illicit drugs and cigarettes). Past-year pregnant and postpartum women were significantly less likely to receive past-year treatment for depression than nonpregnant women although not after adjusting for background sociodemographic characteristics. Conclusions: These results indicate that depression during pregnancy and postpartum is associated with a large range of psychiatric disorders. The high frequency of psychiatric comorbidities, the elevated use of any substances and the high rate of unmet needs should be kept in mind when considering the management of depression during pregnancy and postpartum. © 2011 Elsevier B.V. All rights reserved.


Le Strat Y.,Translational Addiction Research Laboratory | Le Strat Y.,Center for Addiction and Mental Health | Le Strat Y.,French Institute of Health and Medical Research | Le Strat Y.,University Paris Diderot | And 3 more authors.
American Journal of Epidemiology | Year: 2011

The role of cannabis and endocannabinoids in appetite regulation has been extensively studied, but the association of cannabis use with weight in the general population is not known. The authors used data from 2 representative epidemiologic studies of US adults aged 18 years or older, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; 2001-2002) and the National Comorbidity Survey-Replication (NCS-R; 2001-2003), to estimate the prevalence of obesity as a function of cannabis use. The adjusted prevalences of obesity in the NESARC and the NCS-R were 22.0% and 25.3%, respectively, among participants reporting no use of cannabis in the past 12 months and 14.3% and 17.2%, respectively, among participants reporting the use of cannabis at least 3 days per week. These differences were not accounted for by tobacco smoking status. Additionally, after adjustment for sex and age, the use of cannabis was associated with body mass index differences in both samples. The authors conclude that the prevalence of obesity is lower in cannabis users than in nonusers. © 2011 The Author.


Lev-Ran S.,SAMI Health | Lev-Ran S.,Center for Addiction and Mental Health | Lev-Ran S.,Sheba Medical Center | Roerecke M.,Center for Addiction and Mental Health | And 11 more authors.
Psychological Medicine | Year: 2014

Background Longitudinal studies reporting the association between cannabis use and developing depression provide mixed results. The objective of this study was to establish the extent to which different patterns of use of cannabis are associated with the development of depression using meta-analysis of longitudinal studies. Method Peer-reviewed publications reporting the risk of developing depression in cannabis users were located using searches of EMBASE, Medline, PsychINFO and ISI Web of Science. Only longitudinal studies that controlled for depression at baseline were included. Data on several study characteristics, including measures of cannabis use, measures of depression and control variables, were extracted. Odds ratios (ORs) were extracted by age and length of follow-up. Results After screening for 4764 articles, 57 articles were selected for full-text review, of which 14 were included in the quantitative analysis (total number of subjects = 76058). The OR for cannabis users developing depression compared with controls was 1.17 [95% confidence interval (CI) 1.05-1.30]. The OR for heavy cannabis users developing depression was 1.62 (95% CI 1.21-2.16), compared with non-users or light users. Meta-regression revealed no significant differences in effect based on age of subjects and marginal difference in effect based on length of follow-up in the individual studies. There was large heterogeneity in the number and type of control variables in the different studies. Conclusions Cannabis use, and particularly heavy cannabis use, may be associated with an increased risk for developing depressive disorders. There is need for further longitudinal exploration of the association between cannabis use and developing depression, particularly taking into account cumulative exposure to cannabis and potentially significant confounding factors. © Cambridge University Press 2013.


Lev-Ran S.,Translational Addiction Research Laboratory | Lev-Ran S.,Center for Addiction and Mental Health | Imtiaz S.,Translational Addiction Research Laboratory | Rehm J.,Center for Addiction and Mental Health | And 4 more authors.
American Journal on Addictions | Year: 2013

Background and Objectives The association between substance use disorders (SUDs) and mental illness (MI) has been well established. Previous studies reporting this association in various clinical populations have not taken into account former substance use. This may be important as increased prevalence of substance use among individuals with MI may partially explain the strong association between SUDs and MI. Methods In this study we included only individuals with previous substance use and explored the association between lifetime diagnosis of MI and transition from substance use to SUDs. Analyses were conducted across six different categories of substances (alcohol, nicotine, cannabis, cocaine, hallucinogens, inhalants) based on a large representative US sample, the National Epidemiologic Survey of Alcohol and Related Conditions (NESARC, n = 43,093). Results Lifetime diagnoses of any MI, and particularly personality disorders and psychotic disorders, were found to be associated with higher prevalence of transition from substance use to SUDs across most categories of substances. This association was particularly strong for nicotine (adjusted OR = 2.95 (2.72-3.20)). Conclusions and Scientific Significance This cross-sectional study expands on previous research by highlighting the association between lifetime diagnosis of any MI and increased rates of transition from substance use to SUDs across a range of substances. Longitudinal studies exploring temporal effects of this association are further needed. (Am J Addict 2013;22:93-98) © American Academy of Addiction Psychiatry.


Le Foll B.,Translational Addiction Research Laboratory | Le Foll B.,Alcohol Research and Treatment Clinic | Le Foll B.,Campbell Family Mental Health Research Institute | Le Foll B.,University of Toronto | Di Ciano P.,Translational Addiction Research Laboratory
European Neuropsychopharmacology | Year: 2015

Since the cloning of the D3 receptor in the early 1990s, there has been a great deal of interest in this receptor as a possible therapeutic target for drug addiction. The development of a D3 ligand suitable for use in humans has remained elusive, so the study of the function of the D3 receptor and its possible therapeutic efficacy has largely been restricted to animals. Pre-clinical studies have established that systemic administration of D3 ligands, particularly antagonists and partial agonists, can alter drug-seeking in animals. Despite over a decade of research, few studies have investigated the effects of intra-cerebral infusion of D3 ligands on drug-seeking. In the present review, these studies are summarized, which have largely focused on stimulus-controlled behaviors. Converging evidence from studies of D3 receptor expression, Fos and pharmacological Magnetic Resonance Imaging (phMRI) is also provided to delineate some of the D3 brain systems involved in drug-seeking and taking. The data so far indicate that different brain systems may be involved in different types of stimulus control as well as drug taking. © 2014 Elsevier B.V. and ECNP.


Forget B.,Translational Addiction Research Laboratory | Wertheim C.,U.S. National Institute on Drug Abuse | Mascia P.,U.S. National Institute on Drug Abuse | Pushparaj A.,Translational Addiction Research Laboratory | And 3 more authors.
Neuropsychopharmacology | Year: 2010

Nicotine is the main psychoactive ingredient in tobacco and its rewarding effects are considered primarily responsible for persistent tobacco smoking and relapse. Although dopamine has been extensively implicated in the rewarding effects of nicotine, noradrenergic systems may have a larger role than previously suspected. This study evaluated the role of noradrenergic α 1 receptors in nicotine and food self-administration and relapse, nicotine discrimination, and nicotine-induced dopamine release in the nucleus accumbens in rats. We found that the noradrenergic α 1 receptor antagonist prazosin (0.25-1 mg/kg) dose dependently reduced the self-administration of nicotine (0.03 mg/kg), an effect that was maintained over consecutive daily sessions; but did not reduce food self-administration. Prazosin also decreased reinstatement of extinguished nicotine seeking induced by either a nicotine prime (0.15 mg/kg) or nicotine-associated cues, but not food-induced reinstatement of food-seeking, and decreased nicotine-induced (0.15 mg/kg) dopamine release in the nucleus accumbens shell. However, prazosin did not have nicotine-like discriminative effects and did not alter the dose-response curve for nicotine discrimination. These findings suggest that stimulation of noradrenergic α 1 receptors is involved in nicotine self-administration and relapse, possibly via facilitation of nicotine-induced activation of the mesolimbic dopaminergic system. The findings point to α 1 adrenoceptor blockade as a potential new approach to the treatment of tobacco dependence in humans. © 2010 Nature Publishing Group All rights reserved.


Sabioni P.,Translational Addiction Research Laboratory | Di Ciano P.,Translational Addiction Research Laboratory | Le Foll B.,Translational Addiction Research Laboratory | Le Foll B.,Alcohol Research and Treatment Clinic | And 2 more authors.
Progress in Neuro-Psychopharmacology and Biological Psychiatry | Year: 2016

Despite the existence of several treatment options for smoking cessation, the rate of relapse after treatment is very high. We and others have proposed that targeting the dopamine D3 receptor (DRD3) may be a good strategy for treatment of nicotine dependence. In human participants, reintroduction to an environment previously associated with drug-taking may induce relapse. In animals, such phenomenon can be studied using the context-induced reinstatement paradigm. As the role of DRD3 in context-induced reinstatement of nicotine-seeking has not yet been explored, we investigated the effects of different doses of the selective DRD3 antagonist SB-277011-A on this reinstatement. Sprague-Dawley adult rats were first trained to self-administer nicotine and subsequently underwent extinction in a second context for 5-7. days. We evaluated the effect of 1, 3 or 10. mg/kg of SB-277011-A administered prior to the reintroduction to the training context. We used two different designs: 1) a between-subjects design with a unique reinstatement test; and 2) a counterbalanced within-subjects design, with 4 reinstatement tests. Our findings indicate that, in the within-subjects design, the magnitude of responding induced by the context-induced reinstatement of nicotine seeking was robust during the first reinstatement test, but significantly decreased with repeated testing. SB-277011-A (10. mg/kg) blocked context-induced reinstatement of nicotine-seeking at first exposure to the context (between-subjects design), but not after repeated context exposure which produced weaker reinstatement over days. Our results support a role for DRD3 mediating context-induced reinstatement of nicotine seeking, but these effects may not be sustained over time. Further studies should explore this in human participants for validation. © 2015 Elsevier Inc.

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