Neurobiologie de la toxicomanie : avancées récentes et nouvelles stratégies d’intervention

Pendant longtemps, la toxicomanie a été associée sur le plan neurobiologique à la modulation à court terme de différents systèmes de neurotransmission. Les stratégies de traitement ciblaient conséquemment les récepteurs auxquels se lie directement la substance étant source d’abus. Ces approches ont contribué à améliorer le soulagement des symptômes d’intoxication et de sevrage, tout en favorisant l’accès à des services psychosociaux adaptés. Toutefois, les données soulignent, chez certains sous-groupes d’individus, l’efficacité parfois mitigée de ces interventions visant à diminuer de façon soutenue la consommation et les symptômes associés à la toxicomanie, particulièrement le craving. Les avancées récentes en neurosciences ont permis de mieux comprendre les mécanismes neurobiologiques expliquant la vulnérabilité à la rechute. D’une conception essentiellement dopaminergique et striatale, les théories biologiques de la toxicomanie intègrent maintenant la contribution des systèmes glutamatergique, opioïde et endocannabinoïde, de même que l’interaction entre ces différentes composantes au sein des structures corticales et sous-corticales. L’intérêt semble avoir migré des phénomènes neurobiologiques à court terme vers la modulation prolongée du fonctionnement des structures en jeu dans la toxicomanie. Ce changement de paradigmes a mené à l’émergence de plusieurs stratégies thérapeutiques visant à diminuer les risques de rechute en modulant de façon plus spécifique les circuits neuronaux dont le fonctionnement est altéré par la prise chronique de substances. Les systèmes endocannabinoïde et glutamatergique, notamment, apparaissent comme une cible de choix pour le traitement du craving et la prévention de la rechute. Le présent article a pour objectif de résumer certains des plus récents courants en matière de conceptualisation neurobiologique de la toxicomanie de même que les nouvelles pistes de traitement en découlant.For years, the neurobiology of drug addiction was characterized by the short-term modulation of different neurotransmission systems, therapeutic strategies directly targeting the receptors that are bound by substances. These approaches have helped to improve the treatment of drug intoxication and withdrawal, while promoting access to a broad array of psychosocial services. However, the data highlight the mixed effectiveness of these interventions to induce a sustained decrease in consumption and other symptoms of addiction, especially craving, among subgroups of individuals. Recent advances in neuroscience have led to a growing understanding of the neurobiological mechanisms underlying the vulnerability to relapse and other behaviors associated with addiction. The primarily dopaminergic and striatal hypothesis of these phenomena has been replaced by a theory incorporating the contribution of the glutamatergic, endocannabinoid and opioid systems, as well as the interaction between these various components within cortical and sub-cortical structures. The focus has moved from the short-term neurobiological changes to the long-lasting modulation of the structures involved in addiction. This paradigm shift led to the emergence of several therapeutic strategies that aim at reducing the risk of relapse by modulating specific neural circuits whose functions are altered by chronic substance use. The endocannabinoid and glutamate systems, in particular, are promising targets for the treatment of craving and relapse. This article aims to summarize some of the latest trends in the neurobiology of addiction as well as new avenues of treatment.Durante mucho tiempo la toxicomanía estuvo asociada en el plano neurobiológico con la modulación a corto plazo de diferentes sistemas de neurotransmisión. Las estrategias de tratamiento apuntaban, por consiguiente, a los receptores que se vinculan directamente con la sustancia que es el origen del abuso. Estos enfoques contribuyeron a mejorar el alivio de los síntomas de intoxicación y abstinencia, favoreciendo al mismo tiempo el acceso a servicios psicosociales adaptados. Sin embargo, en ciertos grupos de individuos, los datos destacan la eficacia a veces mitigada de estas intervenciones destinadas a disminuir de manera continua el consumo y los síntomas relacionados con la toxicomanía, particularmente el craving. Los recientes progresos de la neurociencia permitieron comprender mejor los mecanismos neurobiológicos que explican la vulnerabilidad ante la recaída. De concepción esencialmente dopaminérgica y estratial, las teorías biológicas de la toxicomanía integran ahora la contribución de los sistemas glutamatérgico, opiáceo y endocanabinoide, así como la interacción entre estos diferentes componentes dentro de las estructuras corticales y subcorticales. El interés parece haberse desplazado de los fenómenos neurobiológicos de corto plazo hacia la modulación prolongada del funcionamiento de las estructuras que están en juego en la toxicomanía. Este cambio de paradigmas condujo al surgimiento de numerosas estratégicas terapéuticas destinadas a disminuir los riesgos de recaída al modular más específicamente los circuitos neuronales cuyo funcionamiento está alterado por el consumo crónico de drogas. Los sistemas endocanabinoide y glutamatérgico, principalmente, aparecen como un objetivo a privilegiar para el tratamiento del craving y la prevención de la recaída. El presente artículo está destinado a resumir algunas de las más recientes corrientes en materia de conceptualización neurobiológica de la toxicomanía y las nuevas vías de tratamiento a las que dichas corrientes dan origen

Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens.

Despite abundant expression of DNA methyltransferases (Dnmts) in brain, the regulation and behavioral role of DNA methylation remain poorly understood. We found that Dnmt3a expression was regulated in mouse nucleus accumbens (NAc) by chronic cocaine use and chronic social defeat stress. Moreover, NAc-specific manipulations that block DNA methylation potentiated cocaine reward and exerted antidepressant-like effects, whereas NAc-specific Dnmt3a overexpression attenuated cocaine reward and was pro-depressant. On a cellular level, we found that chronic cocaine use selectively increased thin dendritic spines on NAc neurons and that DNA methylation was both necessary and sufficient to mediate these effects. These data establish the importance of Dnmt3a in the NAc in regulating cellular and behavioral plasticity to emotional stimuli

Cannabis-Dependence Risk Relates to Synergism between Neuroticism and Proenkephalin SNPs Associated with Amygdala Gene Expression: Case-Control Study

Background Many young people experiment with cannabis, yet only a subgroup progress to dependence suggesting individual differences that could relate to factors such as genetics and behavioral traits. Dopamine receptor D2 (DRD2) and proenkephalin (PENK) genes have been implicated in animal studies with cannabis exposure. Whether polymorphisms of these genes are associated with cannabis dependence and related behavioral traits is unknown. Methodology/Principal Findings Healthy young adults (18–27 years) with cannabis dependence and without a dependence diagnosis were studied (N = 50/group) in relation to a priori-determined single nucleotide polymorphisms (SNPs) of the DRD2 and PENK genes. Negative affect, Impulsive Risk Taking and Neuroticism-Anxiety temperamental traits, positive and negative reward-learning performance and stop-signal reaction times were examined. The findings replicated the known association between the rs6277 DRD2 SNP and decisions associated with negative reinforcement outcomes. Moreover, PENK variants (rs2576573 and rs2609997) significantly related to Neuroticism and cannabis dependence. Cigarette smoking is common in cannabis users, but it was not associated to PENK SNPs as also validated in another cohort (N = 247 smokers, N = 312 non-smokers). Neuroticism mediated (15.3%–19.5%) the genetic risk to cannabis dependence and interacted with risk SNPs, resulting in a 9-fold increase risk for cannabis dependence. Molecular characterization of the postmortem human brain in a different population revealed an association between PENK SNPs and PENK mRNA expression in the central amygdala nucleus emphasizing the functional relevance of the SNPs in a brain region strongly linked to negative affect. Conclusions/Significance Overall, the findings suggest an important role for Neuroticism as an endophenotype linking PENK polymorphisms to cannabis-dependence vulnerability synergistically amplifying the apparent genetic risk

Elucidation of The Behavioral Program and Neuronal Network Encoded by Dorsal Raphe Serotonergic Neurons

Elucidating how the brain's serotonergic network mediates diverse behavioral actions over both relatively short (minutes–hours) and long period of time (days–weeks) remains a major challenge for neuroscience. Our relative ignorance is largely due to the lack of technologies with robustness, reversibility, and spatio-temporal control. Recently, we have demonstrated that our chemogenetic approach (eg, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) provides a reliable and robust tool for controlling genetically defined neural populations. Here we show how short- and long-term activation of dorsal raphe nucleus (DRN) serotonergic neurons induces robust behavioral responses. We found that both short- and long-term activation of DRN serotonergic neurons induce antidepressant-like behavioral responses. However, only short-term activation induces anxiogenic-like behaviors. In parallel, these behavioral phenotypes were associated with a metabolic map of whole brain network activity via a recently developed non-invasive imaging technology DREAMM (DREADD Associated Metabolic Mapping). Our findings reveal a previously unappreciated brain network elicited by selective activation of DRN serotonin neurons and illuminate potential therapeutic and adverse effects of drugs targeting DRN neurons

Histone arginine methylation in cocaine action in the nucleus accumbens

Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanisms - such as histone acetylation and methylation on Lys residues - have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motiv ation to self-administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction. Keywords: histone arginine (R) methylation; drug addiction; medium spiny neurons; ChIP-seq; Sr

Cannabis-Dependence Risk Relates to Synergism between Neuroticism and Proenkephalin SNPs Associated with Amygdala Gene Expression: Case-Control Study

BACKGROUND:Many young people experiment with cannabis, yet only a subgroup progress to dependence suggesting individual differences that could relate to factors such as genetics and behavioral traits. Dopamine receptor D2 (DRD2) and proenkephalin (PENK) genes have been implicated in animal studies with cannabis exposure. Whether polymorphisms of these genes are associated with cannabis dependence and related behavioral traits is unknown. METHODOLOGY/PRINCIPAL FINDINGS:Healthy young adults (18-27 years) with cannabis dependence and without a dependence diagnosis were studied (N = 50/group) in relation to a priori-determined single nucleotide polymorphisms (SNPs) of the DRD2 and PENK genes. Negative affect, Impulsive Risk Taking and Neuroticism-Anxiety temperamental traits, positive and negative reward-learning performance and stop-signal reaction times were examined. The findings replicated the known association between the rs6277 DRD2 SNP and decisions associated with negative reinforcement outcomes. Moreover, PENK variants (rs2576573 and rs2609997) significantly related to Neuroticism and cannabis dependence. Cigarette smoking is common in cannabis users, but it was not associated to PENK SNPs as also validated in another cohort (N = 247 smokers, N = 312 non-smokers). Neuroticism mediated (15.3%-19.5%) the genetic risk to cannabis dependence and interacted with risk SNPs, resulting in a 9-fold increase risk for cannabis dependence. Molecular characterization of the postmortem human brain in a different population revealed an association between PENK SNPs and PENK mRNA expression in the central amygdala nucleus emphasizing the functional relevance of the SNPs in a brain region strongly linked to negative affect. CONCLUSIONS/SIGNIFICANCE:Overall, the findings suggest an important role for Neuroticism as an endophenotype linking PENK polymorphisms to cannabis-dependence vulnerability synergistically amplifying the apparent genetic risk