Regular use of illegal drugs is suspected to cause cognitive impairments. Two substances have received heightened attention: 3,4-methylenedioxymethamphetamine (MDMA or ‘ecstasy’) and δ-9-tetrahydrocannabinol (THC or ‘cannabis’). Preclinical evidence, as well as human studies examining regular ecstasy consumers, indicated that ecstasy use may have negative effects on learning, verbal memory and complex attentional functions. Cannabis has also been linked to symptoms of inattention and deficits in learning and memory. Most of the published studies in this field of research recruited participants by means of newspaper advertisements or by using word-of-mouth strategies. Because participants were usually aware that their drug use was critical to the research design, this awareness may have caused selection bias or created expectation effects. Focussing on attention and memory, this study aimed to assess cognitive functioning in a community-based representative sample that was derived from a large-scale epidemiological study. Available data concerning drug use history allowed sampling of subjects with varying degrees of lifetime drug experiences. Cognitive functioning was examined in 284 young participants, between 22 and 34 years. In general, their lifetime drug experience was moderate. Participants completed a neuropsychological test battery, including measures for verbal learning, memory and various attentional functions. Linear regression analysis was performed to investigate the relationship between cognitive functioning and lifetime experience of drug use. Ecstasy and cannabis use were significantly related to poorer episodic memory function in a dose-related manner. For attentional measures, decrements of small effect sizes were found. Error measures in tonic and phasic alertness tasks, selective attention task and vigilance showed small but significant effects, suggesting a stronger tendency to experience lapses of attention. No indication for differences in reaction time was found. The results are consistent with decrements of memory and attentional performance described in previous studies. These effects are relatively small; however, it must be kept in mind that this study focussed on assessing young adults with moderate drug use from a population-based study.

Objectives: To determine risk factors of incident onset of use, abuse and dependence of cannabis in a community sample of adolescents and young adults. Methods: Risk factors were examined in a prospective longitudinal design across 4 years in a representative sample (N=2446) aged 14-24 at the outset of the study (EDSP). Patterns of DSM-IV defined cannabis use, abuse and dependence were assessed with the Composite International Diagnostic Interview (M-CIDI). Potential risk factors were assessed at baseline. Incident cannabis use, abuse and dependence at second follow-up (on average 42 months after baseline) were the main outcome measures in this study. Associations were analyzed with logistic and negative binomial regressions. Results: Using 11 of a total of 56 variables examined, the predictive value of the final multiple logistic regression for incident cannabis use was moderately good (area under the ROC curve=0.78). Cannabis use frequency was predicted in the final model by 18 variables, cannabis abuse by two variables in the younger subsample and nine factors in the older group, and dependence by eight variables (dependence: ROC curve area=0.97). Incident cannabis use was predicted mainly by availability of drugs, peers’ drug use, a more ‘positive’ attitude towards future drug use, and regular previous use of licit drugs, while cannabis dependence was predicted primarily by parental death before age 15, deprived socio-economic status, and baseline use of other illicit drugs. Conclusion: Different factors predict the onset or severity of cannabis use and the progression to abuse and dependence. In addition to well-documented risk factors such as peer group pressure, drug availability, and low self-esteem, findings suggest that family history (e.g. parental mental disorders, early parental death), and prior experiences with legal drugs play a significant role in the initiation of cannabis consumption and the transition to cannabis use disorders in adolescents and young adults. Findings suggest that early intervention and prevention might be improved by better targeted treatment.

Aim: To examine prospectively over a period of 4 years the profile of cannabis dependence and the risk of specific dependence criteria in a community sample of adolescents. Methods: A representative community sample of 2446 young adults aged 14–24 years at baseline was followed up over a period of 4 years. Frequency of use measures and of criteria for DSM-IV dependence were assessed by standardized diagnostic interview measures (CIDI). To explore the nature of this association, frequency of use and concomitant use of other psychoactive substances was considered. Results: 30% of the sample were cannabis users. Among all users 35% met at least one dependence criterion. Most frequently reported dependence criteria among all users were withdrawal (17%), tolerance (15%), loss of control (14%) and continued use despite a health problem (13%). Even without concomitant use of other illicit drugs, 22% of low frequency users and 81% of high frequency users met at least one dependence criterion. Symptom patterns were similar in high and low frequency users. The occurrence of a dependence syndrome or of specific dependence criteria could not be attributed to the use of other illicit drugs or to comorbid nicotine and alcohol dependence. Conclusions: Regular cannabis use in adolescence is associated with the development of a dependence syndrome. This association cannot be explained by the concomitant use of other illicit substances or by comorbid nicotine and alcohol dependence.

Background: Whereas the role of externalizing disorders is relatively well established in predicting the onset of cannabis use (CU) or cannabis use disorder (CUD), the status of anxiety and mood disorders in predicting CU and CUD remains controversial. Objective: (1) To examine cross-sectional and prospective associations of CU and CUD with a range of mental disorders and whether anxiety and mood disorders are associated with CU/CUD after adjusting for externalizing disorders. Methods: N = 1395 community subjects aged 14–17 at baseline were followed-up at three waves prospectively over 10 years. Substance use, substance disorders and mental disorders were assessed using the DSM-IV/M-CIDI. Results: (1) The baseline prevalence rates where 19.3% at t0 for CU and 2.6% for CUD. Cumulative incidence rates at t3 were 54.3% for CU and 13.7% for CUD. (2) In cross-sectional and prospective analyses other substance use disorders, mood and anxiety disorders were associated with CU and CUD. (3) Associations of panic-anxiety with CU and of depressive and bipolar disorders with CU and CUD were significant after controlling for externalizing disorders. Conclusion: A range of psychopathological conditions, including depressive, bipolar and less consistently anxiety disorders as well as the degree of their comorbidity are significantly associated with incident CU and progression to CUD, even when controlling for externalising disorders. A better understanding of this complex interplay may result in better aetiological models and intervention strategies.

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Contexte Malgré les conséquences néfastes bien connues de la consommation de cannabis chez les patients souffrant de schizophrénie (SCZ), ces derniers en font usage dans une proportion atteignant 40%. Plusieurs études ont tenté d’éclaircir la nature du lien qui existe entre ces deux problématiques, mais cela demeure à ce jour un sujet d’incertitude. Des études précédentes, dont certaines de notre groupe, ont montré que les patients souffrant de schizophrénie et d’un trouble d’abus de cannabis (SCZCAN) présentaient moins de symptômes négatifs, de meilleures capacités cognitives et un processus de traitement des émotions se rapprochant davantage de la normale. Objectif La présente étude vise à évaluer la mémoire émotionnelle ainsi que ses corrélats neurobiologiques par imagerie par résonance magnétique fonctionnelle (IRMf) chez les SCZCAN en comparaison avec les SCZ. Notre hypothèse est que les SCZCAN vont mieux performer lors d’une tâche de mémoire émotionnelle en comparaison avec les SCZ et qu’ils démontreront des activités dans des régions cérébrales plus étendues et impliquées dans la mémoire et le traitement émotionnel. Méthode Trois groupes de sujets, soit un groupe de SCZ (N=14), un groupe de SCZCAN (N=14) et un groupe contrôle (N=21) ont participé à une tâche de mémoire émotionnelle lors d’une imagerie par IRMf. Résultats Les résultats de notre étude ont montré que les SCZCAN performaient mieux que les SCZ dans une tâche de mémoire émotionnelle et montraient des activations dans des régions cérébrales plus étendues à l’IRMf, en particulier celles impliquées dans mémoire et dans le traitement des émotions (cortex orbitofrontal et temporal, hippocampe). Conclusion Les SCZCAN ont une préservation relative de leur mémoire émotionnelle en comparaison aux SCZ, ce qui est corrélé avec de plus grandes activations cérébrales dans les régions qui jouent un rôle dans la mémoire et le traitement émotionnel. / Context In spite of well-known adverse consequences of cannabis consumption in patients with schizophrenia (SCZ), it is recognized that cannabis use reaches levels as high as 40 % in this population. Recently, a number of studies have attempted to get a better grasp of the relationship between these two conditions, which remains unclear to this day. Previous studies, including some from our group, have shown that cannabis abusing patients (SCZCAN) tend to have less prominent negative symptoms, better cognitive abilities, and that their emotion processing is closer to normal. Aim The present study aims to compare emotional memory in patients with schizophrenia with or without cannabis abuse, our hypothesis being that SCZCAN will perform better on an emotional memory task and will activate larger brain regions during functional imaging, as compared to SCZ. Method Three groups of subjects, namely SCZ (N=14), SCZCAN (N=14) and control subjects (N=21) underwent an emotional memory task during a functional magnetic resonance imaging session. Results Our study showed that the group of SCZCAN performed better than SCZ in a functional memory task and activated larger brain regions during functional imaging, in particular those linked to memory and emotional processing (orbitofrontal and temporal cortex, hippocampus). Conclusion The group of SCZCAN demonstrated a relative preservation of their emotional memory as compared to SCZ and activated larger brain regions during functional imaging.

La consommation de cannabis et la conduite sous l’influence du cannabis sont des préoccupations grandissantes dans la société d’aujourd’hui. Le but de la présente étude est d’examiner plus en profondeur la relation entre la fréquence de consommation de cannabis chez les jeunes adultes et la prise de risque sur la route. Les participants (n=48) sont tous des hommes âgés de 18 à 26 ans. Ils ont complété une batterie de questionnaires ainsi qu’une tâche sur simulateur de conduite. Les résultats indiquent que la fréquence de consommation de cannabis est associée positivement avec la prise de risque auto rapportée et suggèrent une tendance positive avec les comportements risqués observés lors de la simulation de conduite en laboratoire. Lorsque les différents groupes de consommateurs sont comparés, ceux qui font un usage quotidien ou multihebdomadaire de cannabis semblent prendre plus de risques au volant que ceux qui consomment une fois semaine et moins ou encore une fois par mois et moins. De plus, il semble que plus les individus consomment fréquemment de la marijuana, plus ils ont tendance à adopter des attitudes permissives en lien avec la conduite sous l’influence de cannabis. Les implications quant à l’intervention sont discutées. / Cannabis use and driving under the influence of cannabis have become a growing concern in today’s society. The aim of the present study was to further examine the relationship between the use frequency of cannabis among young adults and on-road risk taking. Participants (n=48) were all men aged between 18 and 26 years old who were asked to complete questionnaires and to perform in a simulation task. Results indicate that the use frequency of cannabis is positively associated with self-report of risky driving and suggest a trend with observed risk taking behaviour during the simulation. When comparing the different cannabis users, participants who consumed daily or multiple times a week seem to take more risk on the road than those who use cannabis once a week or less and less than monthly. Moreover, it seems that marijuana users who consume more frequently have a tendency of adopting more permissive attitudes toward smoking cannabis and taking the wheel. Implications for interventions are discussed.

La sérotonine est impliquée dans de nombreuses fonctions physiologiques comme la régulation de l’appétit, du sommeil, de la douleur, de l’humeur et de la cognition. Elle agit par l’intermédiaire de différents récepteurs dont la plupart sont couplés aux protéines G. Parmi ceux-ci, les récepteurs 5-HT2A et 5-HT6 suscitent un intérêt particulier car ils sont la cible de nombreux agents thérapeutiques, comme les antidépresseurs et les antipsychotiques de dernière génération. Ces molécules administrées pour traiter la schizophrénie ont des effets bénéfiques sur les symptômes positifs (hallucinations, délires) et négatifs (manque de motivation). Cependant, ils n’ont que peu d’effets sur les déficits cognitifs (troubles de la mémoire de travail, de l’attention, asociabilité) qui compromettent l'intégration sociale et professionnelle des patients ainsi que leur qualité de vie. Ces déficits sont en grande partie retrouvés chez les consommateurs chroniques de cannabis durant l’adolescence suggérant des mécanismes pathologiques communs. La découverte de nouvelles stratégies thérapeutiques pour traiter ces déficits cognitifs constitue donc un enjeu de santé publique majeur.Au cours de mon travail de thèse, j’ai étudié le rôle des récepteurs de la sérotonine, en me focalisant sur les récepteurs 5-HT2A et 5-HT6, dans la modulation de la transmission et la plasticité synaptique au niveau du cortex préfrontal. En combinant des approches biochimiques à des analyses électrophysiologiques et comportementales, j’ai dans un premier temps démontré l'implication des récepteurs 5-HT2A exprimés au niveau des synapses thalamocorticales dans l’induction de la plasticité synaptique et dans la mémoire associative. Dans un deuxième temps, j’ai déterminé les bénéfices du blocage précoce des récepteurs 5-HT6 sur les déficits cognitifs induits dans un modèle neurodéveloppemental de schizophrénie et un modèle de consommation chronique de cannabis durant l’adolescence. Cette étude permet ainsi d’envisager de nouvelles stratégies thérapeutiques pour prévenir l’apparition des déficits cognitifs observés dans les maladies psychiatriques, notamment chez les sujets à risque. / Serotonin is involved in many physiological functions, such as the control of appetite, sleep, pain, mood and cognition. This major neuromodulator acts via different receptors, which are, for the most part, coupled to G-proteins. Among these, 5-HT2A and 5-HT6 receptors are of particular interest since they are the target of many therapeutic drugs, such as antidepressants and last-generation antipsychotics. These are administered to treat schizophrenia and have beneficial effects on positive (hallucinations, delusions) and negative (lack of motivation) symptoms. Nevertheless, they poorly control cognitive deficits (impaired working memory, decreased attention, alteration in social cognition) which severely compromise the social integration of patients and their quality of life. These deficits are also found in chronic cannabis users during adolescence, suggesting common pathological mechanisms. Therefore, the discovery of new therapeutic strategies to treat these cognitive deficits is a major public health issue.During my thesis work, I studied the role of serotonin receptors, focusing on 5-HT2A and 5-HT6 receptors, in the modulation of synaptic transmission and plasticity in the prefrontal cortex. By combining biochemical approaches with electrophysiological and behavioral analyses, I initially demonstrated that 5-HT2A receptors expressed at thalamocortical synapses play a crucial role in the induction of synaptic plasticity and in associative memory. Secondly, I demonstrated the benefits of early blockade of 5-HT6 receptors for preventing cognitive deficits induced in a neurodevelopmental model of schizophrenia and a model of chronic cannabis abuse during adolescence. These studies offer new therapeutic strategies to prevent the emergence of cognitive deficits and conversion to schizophrenia in at-risk subjects.

S’il est actuellement reconnu qu’un ensemble de facteurs vulnérabilisant et protecteurs interagissent dans les processus d’instauration des conduites de dépendance alcoolique et cannabique à l’adolescence, les connaissances sont encore peu avancées concernant la manière dont ils s’articulent. Parmi ces facteurs, certains traits de personnalité, l’estime de soi et les difficultés interpersonnelles, sont considérés comme majeurs. L’introduction théorique de notre travail tente de mettre en évidence l’intérêt de retenir la théorie des Big Five (Goldberg, 1993; John & Srivastava, 1999) dans l’étude de ces conduites, car elle est considérée actuellement comme une taxonomie rigoureuse, connaissant un large consensus dans le domaine de la psychologie de la personnalité (McAdams & Pals, 2006). Dans cette même partie, nous soulignons l’intérêt de s’appuyer sur une conception multi-dimensionnelle de l’estime de soi, afin de l’inscrire dans une approche globale. Enfin, nous y distinguons différents domaines liés aux difficultés interpersonnelles à l’adolescence, tels que l’affirmation de soi, les relations familiales, les relations aux pairs, les relations amicales et les relations sentimentales / Even though it is now commonly acknowldged that a set of destabilising and protecting factors are at play in the appearance of alcohol and cannabis dependence in adolescents, there is as of yet little knowledge of how these factors actually interact. Amongst the latter, certain personality traits, self-esteem and interpersonal difficulties are considered key. The theoretical introduction to our work aims at underlining the importance of the theory of the Big Five (Goldberg, 1993; John & Srivastava, 1999) in this field, this model being currently considered a rigorous taxonomy that gathers a large consensus in the field of personality psychology (McAdams & Pals, 2006). In the introduction as well, we stress the relevance of a multi-dimensional conception of self-esteem, so as to frame it as part of a wider approach. Finally, we establish different areas related to interpersonal difficulties in adolescents, such as self-assertion, family relations, relations with peers, love relationships and friendship