A phosphatase cascade by which rewarding stimuli control nucleosomal response

ArticleInternational audienceDopamine orchestrates motor behaviour and reward-driven learning. Perturbations of dopamine signalling have been implicated in several neurological and psychiatric disorders, and in drug addiction. The actions of dopamine are mediated in part by the regulation of gene expression in the striatum, through mechanisms that are not fully understood. Here we show that drugs of abuse, as well as food reinforcement learning, promote the nuclear accumulation of 32-kDa dopamine-regulated and cyclic-AMP-regulated phosphoprotein (DARPP-32). This accumulation is mediated through a signalling cascade involving dopamine D1 receptors, cAMP-dependent activation of protein phosphatase-2A, dephosphorylation of DARPP-32 at Ser 97 and inhibition of its nuclear export. The nuclear accumulation of DARPP-32, a potent inhibitor of protein phosphatase-1, increases the phosphorylation of histone H3, an important component of nucleosomal response. Mutation of Ser 97 profoundly alters behavioural effects of drugs of abuse and decreases motivation for food, underlining the functional importance of this signalling cascad

Cocaine-evoked negative symptoms require AMPA receptor trafficking in the lateral habenula

International audienc

RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release

The firing of mesolimbic dopamine neurons is important for drug-induced reinforcement, although underlying genetic factors remain poorly understood. In a recent genome-wide association metaanalysis of alcohol intake, we identified a suggestive association of SNP rs26907 in the ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) gene, encoding a protein that mediates Ca(2+)-dependent activation of the ERK pathway. We performed functional characterization of this gene in relation to alcohol-related phenotypes and mesolimbic dopamine function in both mice and adolescent humans. Ethanol intake and preference were decreased in Rasgrf2(−/−) mice relative to WT controls. Accordingly, ethanol-induced dopamine release in the ventral striatum was blunted in Rasgrf2(−/−) mice. Recording of dopamine neurons in the ventral tegmental area revealed reduced excitability in the absence of Ras-GRF2, likely because of lack of inhibition of the I(A) potassium current by ERK. This deficit provided an explanation for the altered dopamine release, presumably linked to impaired activation of dopamine neurons firing. Functional neuroimaging analysis of a monetary incentive–delay task in 663 adolescent boys revealed significant association of ventral striatal activity during reward anticipation with a RASGRF2 haplotype containing rs26907, the SNP associated with alcohol intake in our previous metaanalysis. This finding suggests a link between the RASGRF2 haplotype and reward sensitivity, a known risk factor for alcohol and drug addiction. Indeed, follow-up of these same boys at age 16 y revealed an association between this haplotype and number of drinking episodes. Together, these combined animal and human data indicate a role for RASGRF2 in the regulation of mesolimbic dopamine neuron activity, reward response, and alcohol use and abuse

RASGRF2 regulates alcohol-induced reinforcement by influencing mesolimbic dopamine neuron activity and dopamine release

[ES]La activación de las neuronas dopaminérgicas mesolímbicas es importante para el refuerzo inducido por fármacos, aunque los factores genéticos subyacentes siguen siendo poco conocidos. En un reciente metaanálisis de asociación de todo el genoma de la ingesta de alcohol, identificamos una sugerente asociación del SNP rs26907 en el gen del factor liberador de nucleótidos de guanina específico de ras 2 (RASGRF2), que codifica una proteína que media la activación dependiente de Ca2+ de la vía ERK. Realizamos una caracterización funcional de este gen en relación con los fenotipos relacionados con el alcohol y la función de la dopamina mesolímbica tanto en ratones como en humanos adolescentes. La ingesta y la preferencia de etanol disminuyeron en los ratones Rasgrf2-/- en comparación con los controles WT. En consecuencia, la liberación de dopamina inducida por etanol en el cuerpo estriado ventral se redujo en ratones Rasgrf2-/-. El registro de neuronas de dopamina en el área tegmental ventral reveló una excitabilidad reducida en ausencia de Ras-GRF2, probablemente debido a la falta de inhibición de la corriente de potasio IA por parte de ERK. Este déficit proporcionó una explicación para la liberación alterada de dopamina, presumiblemente relacionada con una activación deficiente de las neuronas de dopamina que se activan. El análisis de neuroimagen funcional de una tarea de incentivo-retraso monetario en 663 adolescentes reveló una asociación significativa de la actividad estriada ventral durante la anticipación de la recompensa con un haplotipo RASGRF2 que contiene rs26907, el SNP asociado con la ingesta de alcohol en nuestro metaanálisis anterior. Este hallazgo sugiere un vínculo entre el haplotipo RAGRF2 y la sensibilidad a la recompensa, un factor de riesgo conocido para la adicción al alcohol y las drogas. De hecho, el seguimiento de estos mismos chicos a los 16 años reveló una asociación entre este haplotipo y el número de episodios de consumo de alcohol. En conjunto, estos datos combinados de animales y humanos indican un papel de RASGRF2 en la regulación de la actividad de las neuronas dopaminérgicas mesolímbicas, la respuesta de recompensa y el uso y abuso de alcohol.[EN]The firing of mesolimbic dopamine neurons is important for drug-induced reinforcement, although underlying genetic factors remain poorly understood. In a recent genome-wide association metaanalysis of alcohol intake, we identified a suggestive association of SNP rs26907 in the ras-specific guanine-nucleotide releasing factor 2 (RASGRF2) gene, encoding a protein that mediates Ca2+-dependent activation of the ERK pathway. We performed functional characterization of this gene in relation to alcohol-related phenotypes and mesolimbic dopamine function in both mice and adolescent humans. Ethanol intake and preference were decreased in Rasgrf2−/− mice relative to WT controls. Accordingly, ethanol-induced dopamine release in the ventral striatum was blunted in Rasgrf2−/− mice. Recording of dopamine neurons in the ventral tegmental area revealed reduced excitability in the absence of Ras-GRF2, likely because of lack of inhibition of the IA potassium current by ERK. This deficit provided an explanation for the altered dopamine release, presumably linked to impaired activation of dopamine neurons firing. Functional neuroimaging analysis of a monetary incentive–delay task in 663 adolescent boys revealed significant association of ventral striatal activity during reward anticipation with a RASGRF2 haplotype containing rs26907, the SNP associated with alcohol intake in our previous metaanalysis. This finding suggests a link between the RASGRF2 haplotype and reward sensitivity, a known risk factor for alcohol and drug addiction. Indeed, follow-up of these same boys at age 16 y revealed an association between this haplotype and number of drinking episodes. Together, these combined animal and human data indicate a role for RASGRF2 in the regulation of mesolimbic dopamine neuron activity, reward response, and alcohol use and abuse.Este trabajo fue apoyado por subvenciones del FIS (Fondo de Investigación Sanitaria) [PS09/01979]; RTICC (Red Temática de Investigación Cooperativa en Cáncer) [RD06/0020/000], y JCYL (Junta de Castilla y León) [SA044A08 y GR93]