Cocaine Is Low on the Value Ladder of Rats: Possible Evidence for Resilience to Addiction

International audienceBACKGROUND:Assessing the relative value of cocaine and how it changes with chronic drug use represents a long-standing goal in addiction research. Surprisingly, recent experiments in rats--by far the most frequently used animal model in this field--suggest that the value of cocaine is lower than previously thought.METHODOLOGY/PRINCIPAL FINDINGS:Here we report a series of choice experiments that better define the relative position of cocaine on the value ladder of rats (i.e., preference rank-ordering of different rewards). Rats were allowed to choose either taking cocaine or drinking water sweetened with saccharin--a nondrug alternative that is not biologically essential. By systematically varying the cost and concentration of sweet water, we found that cocaine is low on the value ladder of the large majority of rats, near the lowest concentrations of sweet water. In addition, a retrospective analysis of all experiments over the past 5 years revealed that no matter how heavy was past cocaine use most rats readily give up cocaine use in favor of the nondrug alternative. Only a minority, fewer than 15% at the heaviest level of past cocaine use, continued to take cocaine, even when hungry and offered a natural sugar that could relieve their need of calories.CONCLUSIONS/SIGNIFICANCE:This pattern of results (cocaine abstinence in most rats; cocaine preference in few rats) maps well onto the epidemiology of human cocaine addiction and suggests that only a minority of rats would be vulnerable to cocaine addiction while the large majority would be resilient despite extensive drug use. Resilience to drug addiction has long been suspected in humans but could not be firmly established, mostly because it is difficult to control retrospectively for differences in drug self-exposure and/or availability in human drug users. This conclusion has important implications for preclinical research on the neurobiology of cocaine addiction and for future medication development

Tonic role of CB1 receptors in the emotional consequences of physical exercise and repeated stress

Le système endocannabinoïde régule de nombreuses fonctions physiologiques. Dans le cerveau, cette régulation est exercée principalement par l’activation des récepteurs CB1. En effet, ces derniers jouent un rôle clef dans la régulation des neurotransmissions excitatrices et inhibitrices, y compris dans des régions cérébrales impliquées dans la gestion des processus émotionnels. Les données existantes indiquent que les récepteurs CB1 exercent un contrôle tonique sur certaines dimensions de l’émotion (e.g. anxiété, peur), mais le rôle joué par ces récepteurs dans les conséquences émotionnelles de l’exposition répétée à des stimuli attractifs ou aversifs n’a été que peu analysé. L’objectif de nos travaux a donc été d’examiner chez la souris le rôle des récepteurs CB1 (i) dans l’adhérence à un exercice physique volontaire répété, et dans les impacts émotionnels (ii) de l’exercice volontaire répété, et (iii) du stress par défaites sociales répété. Cet examen a été réalisé principalement à l’aide d’outils génétiques (mutants constitutifs et conditionnels du récepteur CB1) mais également à l’aide d’outils pharmacologiques (antagonistes sélectifs des récepteurs CB1). L’utilisation de ces outils nous a permis d’identifier un rôle spécifique des récepteurs CB1 des neurones GABAergiques de l’aire tegmentale ventrale dans le contrôle des performances d’exercice physique volontaire sur roue chez la souris. De plus, les données comportementales obtenues indiquent que les récepteurs CB1 portés par les neurones glutamatergiques corticaux jouent un rôlecrucial dans les profils d’anxiété et d’extinction de peur observés après un exercice physique volontaire répété. Enfin, une dernière série d’études a permis de distinguer les impacts respectifs del’enrichissement de l’hébergement d’une part, et de la pratique de l’exercice d’autre part, dans les conséquences de l’exercice volontaire sur les comportements émotionnels et la neurogenèse hippocampique.Un second volet de recherche a permis de définir les rôles respectifs des récepteurs CB1 portés pardifférentes populations neuronales dans l’impact psychoneuroendocrinien (comportement, métabolisme, réactivité corticotrope) du stress social par défaites répétées. En particulier, ce travail asouligné l’impact majeur des récepteurs CB1 des neurones sérotonergiques dans les modifications depoids corporel et d’appétence pour le sucre induites par le stress répété. De plus, les résultats obtenus chez des animaux contrôles et des animaux stressés ont mis en avant le rôle des récepteursCB1 des neurones glutamatergiques corticaux et des neurones exprimant le facteur Sim1 (i.e. majoritairement hypothalamiques) dans les processus d’extinction de la mémoire de peur conditionnée au son.The endocannabinoid system regulates a plethora of physiological functions. In the central nervoussystem, such a regulation is mainly achieved through the stimulation of CB1 receptors. Thus, these receptors exert a key control over excitatory and inhibitory transmissions, including in brain areas ubserving emotional processes. The data gathered so far have provided evidence for a tonic controlof several dimensions of emotionality (e.g. anxiety, fear) by CB1 receptors, but the role played by these receptors in the emotional consequences of the repeated exposure to positive or to negative stimuli has been poorly addressed. Thus, the aims of this work were to examine the role of CB1 receptors (i) in voluntary exercise (wheel running) performance, and in several emotional effects of(ii) repeated voluntary exercise and (iii) repeated social stress in mice. This task was mainly achievedthrough the use of genetic (constitutive and conditional CB1 receptor mutants) and, albeit to a lowerextent, pharmacological (CB1 receptor antagonists) tools.The aforementioned tools allowed us to assign to CB1 receptors located on ventral tegmental area GABAergic neurons a tonic stimulatory influence on voluntary running performance. Moreover, behavioural experiments led us to conclude that CB1 receptors located on cortical glutamatergic neurons are involved in the anxiety and fear extinction patterns observed in animals given repeatedaccess to exercise. Lastly, a series of studies allowed us to distinguish between the respective impacts of housing enrichment and exercise in the consequences of wheel running on emotional behaviours and hippocampal neurogenesis.A second set of experiments defined the respective roles played by distinct neuronal CB1 receptor populations in the psychoneuroendocrine effects of repeated social stress. Thus, this work presentedevidence for a tonic role exerted by CB1 receptors located on central serotonergic neurones in stresselicited changes in body weight growth and hedonia for sucrose. Besides, CB1 receptors located on cortical glutamatergic neurons or on Sim1-expressing neurons (which are mainly present in the paraventricular hypothalamus) were found to exert major roles in the extinction of cued fear memory in unstressed and/or stressed animals

Tonic role of CB1 receptors in the emotional consequences of physical exercise and repeated stress

Le système endocannabinoïde régule de nombreuses fonctions physiologiques. Dans le cerveau, cette régulation est exercée principalement par l’activation des récepteurs CB1. En effet, ces derniers jouent un rôle clef dans la régulation des neurotransmissions excitatrices et inhibitrices, y compris dans des régions cérébrales impliquées dans la gestion des processus émotionnels. Les données existantes indiquent que les récepteurs CB1 exercent un contrôle tonique sur certaines dimensions de l’émotion (e.g. anxiété, peur), mais le rôle joué par ces récepteurs dans les conséquences émotionnelles de l’exposition répétée à des stimuli attractifs ou aversifs n’a été que peu analysé. L’objectif de nos travaux a donc été d’examiner chez la souris le rôle des récepteurs CB1 (i) dans l’adhérence à un exercice physique volontaire répété, et dans les impacts émotionnels (ii) de l’exercice volontaire répété, et (iii) du stress par défaites sociales répété. Cet examen a été réalisé principalement à l’aide d’outils génétiques (mutants constitutifs et conditionnels du récepteur CB1) mais également à l’aide d’outils pharmacologiques (antagonistes sélectifs des récepteurs CB1). L’utilisation de ces outils nous a permis d’identifier un rôle spécifique des récepteurs CB1 des neurones GABAergiques de l’aire tegmentale ventrale dans le contrôle des performances d’exercice physique volontaire sur roue chez la souris. De plus, les données comportementales obtenues indiquent que les récepteurs CB1 portés par les neurones glutamatergiques corticaux jouent un rôlecrucial dans les profils d’anxiété et d’extinction de peur observés après un exercice physique volontaire répété. Enfin, une dernière série d’études a permis de distinguer les impacts respectifs del’enrichissement de l’hébergement d’une part, et de la pratique de l’exercice d’autre part, dans les conséquences de l’exercice volontaire sur les comportements émotionnels et la neurogenèse hippocampique.Un second volet de recherche a permis de définir les rôles respectifs des récepteurs CB1 portés pardifférentes populations neuronales dans l’impact psychoneuroendocrinien (comportement, métabolisme, réactivité corticotrope) du stress social par défaites répétées. En particulier, ce travail asouligné l’impact majeur des récepteurs CB1 des neurones sérotonergiques dans les modifications depoids corporel et d’appétence pour le sucre induites par le stress répété. De plus, les résultats obtenus chez des animaux contrôles et des animaux stressés ont mis en avant le rôle des récepteursCB1 des neurones glutamatergiques corticaux et des neurones exprimant le facteur Sim1 (i.e. majoritairement hypothalamiques) dans les processus d’extinction de la mémoire de peur conditionnée au son.The endocannabinoid system regulates a plethora of physiological functions. In the central nervoussystem, such a regulation is mainly achieved through the stimulation of CB1 receptors. Thus, these receptors exert a key control over excitatory and inhibitory transmissions, including in brain areas ubserving emotional processes. The data gathered so far have provided evidence for a tonic controlof several dimensions of emotionality (e.g. anxiety, fear) by CB1 receptors, but the role played by these receptors in the emotional consequences of the repeated exposure to positive or to negative stimuli has been poorly addressed. Thus, the aims of this work were to examine the role of CB1 receptors (i) in voluntary exercise (wheel running) performance, and in several emotional effects of(ii) repeated voluntary exercise and (iii) repeated social stress in mice. This task was mainly achievedthrough the use of genetic (constitutive and conditional CB1 receptor mutants) and, albeit to a lowerextent, pharmacological (CB1 receptor antagonists) tools.The aforementioned tools allowed us to assign to CB1 receptors located on ventral tegmental area GABAergic neurons a tonic stimulatory influence on voluntary running performance. Moreover, behavioural experiments led us to conclude that CB1 receptors located on cortical glutamatergic neurons are involved in the anxiety and fear extinction patterns observed in animals given repeatedaccess to exercise. Lastly, a series of studies allowed us to distinguish between the respective impacts of housing enrichment and exercise in the consequences of wheel running on emotional behaviours and hippocampal neurogenesis.A second set of experiments defined the respective roles played by distinct neuronal CB1 receptor populations in the psychoneuroendocrine effects of repeated social stress. Thus, this work presentedevidence for a tonic role exerted by CB1 receptors located on central serotonergic neurones in stresselicited changes in body weight growth and hedonia for sucrose. Besides, CB1 receptors located on cortical glutamatergic neurons or on Sim1-expressing neurons (which are mainly present in the paraventricular hypothalamus) were found to exert major roles in the extinction of cued fear memory in unstressed and/or stressed animals

CB1 receptor deficiency decreases wheel-running activity: Consequences on emotional behaviours and hippocampal neurogenesis

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Toward recovery-oriented perinatal healthcare: A participatory qualitative exploration of persons with lived experience and health providers’ views and experiences

Abstract Background Perinatal mental health disorders (PMHD) remain often undetected, undiagnosed, and untreated with variable access to perinatal mental health care (PMHC). To guide the design of optimal PMHC (i.e., coproduced with persons with lived experience [PLEs]), this qualitative participatory study explored the experiences, views, and expectations of PLEs, obstetric providers (OP), childcare health providers (CHPs), and mental health providers (MHPs) on PMHC and the care of perinatal depression. Methods We conducted nine focus groups and 24 individual interviews between December 2020 and May 2022 for a total number of 84 participants (24 PLEs; 30 OPs; 11 CHPs; and 19 MHPs). The PLEs group included women with serious mental illness (SMI) or autistic women who had contact with perinatal health services. We recruited PLEs through social media and a center for psychiatric rehabilitation, and health providers (HPs) through perinatal health networks. We used the inductive six-step process by Braun and Clarke for the thematic analysis. Results We found some degree of difference in the identified priorities between PLEs (e.g., personal recovery, person-centered care) and HPs (e.g., common culture, communication between providers, and risk management). Personal recovery in PMHD corresponded to the CHIME framework, that is, connectedness, hope, identity, meaning, and empowerment. Recovery-supporting relations and peer support contributed to personal recovery. Other factors included changes in the socio-cultural conception of the peripartum, challenging stigma (e.g., integrating PMH into standard perinatal healthcare), and service integration. Discussion This analysis generated novel insights into how to improve PMHC for all users including those with SMI or autism

Running per se stimulates the dendritic arbor of newborn dentate granule cells in mouse hippocampus in a duration-dependent manner

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Ventral Tegmental Area Cannabinoid Type-1 Receptors Control Voluntary Exercise Performance

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Relationship between neurocognition and theory of mind as a function of symptomatic profile in schizophrenia: results from the national FACE-SZ cohort

Introduction: Deficits in theory of mind (ToM) can vary depending on the predominant schizophrenia symptoms, and though most neurocognitive functions are involved in ToM, all may not be associated with the same symptoms. With consideration to the relationships between symptoms, neurocognition and ToM, the aim of the present study is to identify the neurocognitive functions influencing ToM capacities according to symptomatic profile. Methods: The study is based on a sample of 124 adults with schizophrenia from a French national cohort. Patients were divided into two groups according to their scores on the five Wallwork factors of the Positive and Negative Syndrome Scale using hierarchical clustering before carrying out multivariable analyses. Results: The “disorganised group” (n = 89) showed high scores on the disorganised factor, and had a ToM associated with reasoning, visual recognition and speed of processing. The “positive group” (n = 35) showed high scores on the positive and depressive factors, and had a ToM associated with working memory. Conclusions: These results suggest that neurocognitive predictors of ToM in schizophrenia are different according to the predominant clinical dimension, thus refining our knowledge of the relationship between symptoms, neurocognition and ToM, and acknowledging their status as important predictors of patients’ functional status. © 2021 Informa UK Limited, trading as Taylor & Francis Group

Genetic Dissection of the Role of Cannabinoid Type-1 Receptors in the Emotional Consequences of Repeated Social Stress in Mice.

International audienceThe endocannabinoid system (ECS) tightly controls emotional responses to acute aversive stimuli. Repeated stress alters ECS activity but the role played by the ECS in the emotional consequences of repeated stress has not been investigated in detail. This study used social defeat stress, together with pharmacology and genetics to examine the role of cannabinoid type-1 (CB(1)) receptors on repeated stress-induced emotional alterations. Seven daily social defeat sessions increased water (but not food) intake, sucrose preference, anxiety, cued fear expression, and adrenal weight in C57BL/6N mice. The first and the last social stress sessions triggered immediate brain region-dependent changes in the concentrations of the principal endocannabinoids anandamide and 2-arachidonoylglycerol. Pretreatment before each of the seven stress sessions with the CB(1) receptor antagonist rimonabant prolonged freezing responses of stressed mice during cued fear recall tests. Repeated social stress abolished the increased fear expression displayed by constitutive CB(1) receptor-deficient mice. The use of mutant mice lacking CB(1) receptors from cortical glutamatergic neurons or from GABAergic neurons indicated that it is the absence of the former CB(1) receptor population that is responsible for the fear responses in socially stressed CB(1) mutant mice. In addition, stress-induced hypolocomotor reactivity was amplified by the absence of CB(1) receptors from GABAergic neurons. Mutant mice lacking CB(1) receptors from serotonergic neurons displayed a higher anxiety but decreased cued fear expression than their wild-type controls. These mutant mice failed to show social stress-elicited increased sucrose preference. This study shows that (i) release of endocannabinoids during stress exposure impedes stress-elicited amplification of cued fear behavior, (ii) social stress opposes the increased fear expression and delayed between-session extinction because of the absence of CB(1) receptors from cortical glutamatergic neurons, and (iii) CB(1) receptors on central serotonergic neurons are involved in the sweet consumption response to repeated stress.Neuropsychopharmacology advance online publication, 21 March 2012; doi:10.1038/npp.2012.36