Modulation and functions of dopamine receptor heteromers in drugs of abuse-induced adaptations

Drug addiction is a chronic and relapsing disorder that leads to compulsive drug intake despite deleterious consequences. By increasing dopamine (DA) in the mesolimbic system, drugs of abuse hijack the brain reward circuitry, which is critical for the development of enduring behavioral alterations. DA mainly acts onto DA D1 (D1R) and D2 (D2R) receptor subtypes, which are positively and negatively coupled to adenylyl cyclase, respectively. Extensive research has aimed at targeting these receptors for the treatment of addiction, however this often results in unwanted side-effects due to the implication of DA receptors in numerous physiological functions. A growing body of evidence indicates that the physical interaction of DA receptors with other receptors can finely tune their function, making DA receptor heteromers promising targets for more specific treatment strategies. An increasing number of articles highlighted the ability of both D1R and D2R to form heteromers, however, most studies carried out to date stem from observations in heterologous systems and the biological significance of DA receptor heteromers in vivo is only emerging. We focused this review on studies that were able to provide insights into functions on D1R and D2R heteromers in drug-evoked adaptations and discuss the limitations of current approaches to study receptor heteromers in vivo. This article is part of the Special Issue entitled 'Receptor heteromers and their allosteric receptor-receptor interactions'.Rôle des heteromères formés par les récepteurs dopamine-glutamate et de signalisation dépendante du calcium nucléaire associée dans l'addictionImpact de la composition lipidique membranaire sur la transmission dopaminergique dépendante du récepteur D2 et la motivationProgram Initiative d’Excellenc

Rôle des hétéromères DAR/NMDAR et de la signalisation nucléaire dépendante du calcium dans les adaptations induites par la cocaïne

Les drogues d'abus augmentent la dopamine (DA) dans le système mésolimbique, ce qui altère de manière persistante la transmission du glutamate (Glu) et déclenche des adaptations comportementales durables. L'intégration des signaux DA et Glu dans le striatum est réalisée par les récepteurs DA et Glu présents dans les neurones épineux de taille moyenne (MSN). Notre laboratoire a montré que l'interaction physique entre le récepteur DA (DAR) et la sous-unité GluN1 des récepteurs de glutamate NMDA (NMDAR) était nécessaire pour la facilitation des fonctions des NMDAR par DA. Dans cette étude, nous avons montré que le blocage de l'interaction physique entre le DAR et le NMDAR in vivo modifie les effets sensibilisants et gratifiants de la cocaïne. De plus, le blocage de l'interaction entre DAR et GluN1 modifie également la facilitation de l'afflux de Ca2+ dépendant de NMDAR vers le noyau par DA. La signalisation dépendante du calcium nucléaire (nucl-Ca2+) est une voie clé reliant les changements d'activité neuronale à la transcription des gènes dans plusieurs modèles de neuroadaptations de longue durée, mais son rôle en réponse aux drogues d'abus est inconnu. Dans cette thèse, nous avons montré que la signalisation dépendante du nuclé-Ca2+ a un rôle central dans les adaptations moléculaires, cellulaires et comportementales induites par la cocaïne, contribuant ainsi à une meilleure compréhension des bases moléculaires de l'addiction.Drugs of abuse hijack reward processing by increasing dopamine (DA) in the mesolimbic system, especially in the striatum, which persistently alters glutamate (Glu) transmission and triggers long-lasting behavioral adaptations. The integration of DA and Glu signals in the striatum is achieved by DA and Glu receptors present in medium-size spiny neurons (MSN). Our laboratory has previously shown that the physical interaction between DA receptor (DAR) and GluN1 subunit of glutamate NMDA receptors (NMDAR) was necessary for the facilitation of NMDAR functions by DA. In this study, we showed that blocking the physical interaction between DAR and NMDAR in vivo alters the sensitizing and rewarding effects of cocaine. Moreover, blocking DAR and GluN1 interaction also alters the facilitation of NMDAR-dependent Ca2+ influx towards the nucleus by DA. Nuclear calcium (nucl-Ca2+) dependent signaling is a key route linking neuronal activity changes to gene transcription in multiple models of long-lasting neuroadaptations, but its role in response to drugs of abuse is unknown. In this thesis, we showed that nucl-Ca2+ dependent signaling has a central role in cocaine-induced molecular, cellular and behavioral adaptations, therefore contributing to a better understanding of the molecular basis of addiction

Activity-Regulated Cytoskeleton-Associated Protein Accumulates in the Nucleus in Response to Cocaine and Acts as a Brake on Chromatin Remodeling and Long-Term Behavioral Alterations

International audienceBACKGROUND: Addiction relies on persistent alterations of neuronal properties, which depends on gene regulation. Activity-regulated cytoskeleton-associated protein (Arc) is an immediate early gene that modulates neuronal plasticity underlying learning and memory. Its role in cocaine-induced neuronal and behavioral adaptations remains elusive. METHODS: Acute cocaine-treated mice were used for quantitative reverse-transcriptase polymerase chain reaction, immunocytochemistry, and confocal imaging from striatum. Live imaging and transfection assays for Arc overexpression were performed from primary cultures. Molecular and behavioral adaptations to cocaine were studied from Arc-deficient mice and their wild-type littermates. RESULTS: Arc messenger RNA and proteins are rapidly induced in the striatum after acute cocaine administration, via an extracellular-signal regulated kinase-dependent de novo protein synthesis. Although detected in dendrites, Arc accumulates in the nucleus in active zones of transcription, where it colocalizes with phosphorylated histone-H3, an important component of nucleosomal response. In vitro, Arc overexpression downregulates phosphorylated histone-H3 without modifying extracellular-signal regulated kinase phosphorylation in the nucleus. In vivo, Arc-deficient mice display decreased heterochromatin domains, a high RNA-polymerase II activity and enhanced c-Fos expression. These mice presented an exacerbated psychomotor sensitization and conditioned place preference induced by low doses of cocaine. CONCLUSIONS: Cocaine induces the rapid induction of Arc and its nuclear accumulation in striatal neurons. Locally, it alters the nucleosomal response, and acts as a brake on chromatin remodeling and gene regulation. These original observations posit Arc as a major homeostatic modulator of molecular and behavioral responses to cocaine. Thus, modulating Arc levels may provide promising therapeutic approaches in drug addiction

Activity-Regulated Cytoskeleton-Associated Protein Accumulates in the Nucleus in Response to Cocaine and Acts as a Brake on Chromatin Remodeling and Long-Term Behavioral Alterations

International audienceBackgroundAddiction relies on persistent alterations of neuronal properties, which depends on gene regulation. Activity-regulated cytoskeleton-associated protein (Arc) is an immediate early gene that modulates neuronal plasticity underlying learning and memory. Its role in cocaine-induced neuronal and behavioral adaptations remains elusive.MethodsAcute cocaine-treated mice were used for Q-RT-PCR, immunocytochemistry and confocal imaging from striatum. Live imaging and transfection assays for Arc overexpression were performed from primary cultures. Molecular and behavioral adaptations to cocaine were studied from Arc-deficient mice and their wild-type littermates.ResultsArc mRNA and proteins are rapidly induced in the striatum after acute cocaine administration, via an ERK-dependent de novo protein synthesis. Although detected in dendrites, Arc accumulates in the nucleus in active zones of transcription where it colocalizes with phosphorylated histone-H3 (pH3), an important component of nucleosomal response. In vitro, Arc overexpression down-regulates pH3 without modifying ERK phosphorylation in the nucleus. In vivo, Arc-deficient mice display decreased heterochromatin domains, a high RNA-Pol II activity and enhanced c-Fos expression. These mice presented an exacerbated psychomotor sensitization and conditioned place preference induced by low doses of cocaine.ConclusionsCocaine induces the rapid induction of Arc and its nuclear accumulation in striatal neurons. Locally, it alters the nucleosomal response, and acts as a brake on chromatin remodeling and gene regulation. These original observations posit Arc as a major homeostatic modulator of molecular and behavioral responses to cocaine. Thus, modulating Arc levels may provide promising therapeutic approaches in drug addiction

Npas4 regulates medium spiny neuron physiology and gates cocaine‐induced hyperlocomotion

International audienceWe show here that the transcription factor Npas4 is an important regulator of medium spiny neuron spine density and electrophysiological parameters and that it determines the magnitude of cocaineinduced hyperlocomotion in mice. Npas4 is induced by synaptic stimuli that cause calcium influx, but not dopaminergic or PKA-stimulating input, in mouse medium spiny neurons and human iPSC-derived forebrain organoids. This induction is independent of ubiquitous kinase pathways such as PKA and MAPK cascades, and instead depends on calcineurin and nuclear calcium signalling. Npas4 controls a large regulon containing transcripts for synaptic molecules, such as NMDA receptors and VDCC subunits, and determines in vivo MSN spine density, firing rate, I/O gain function and paired-pulse facilitation. These functions at the molecular and cellular levels control the locomotor response to drugs of abuse, as Npas4 knockdown in the nucleus accumbens decreases hyperlocomotion in response to cocaine in male mice while leaving basal locomotor behaviour unchanged

SWI/SNF chromatin remodeler complex within the reward pathway is required for behavioral adaptations to stress

Stress exposure is a cardinal risk factor for most psychiatric diseases. Preclinical and clinical studies point to changes in gene expression involving epigenetic modifications within mesocorticolimbic brain circuits. Brahma (BRM) and Brahma-Related-Gene-1 (BRG1) are ATPase subunits of the SWI/SNF complexes involved in chromatin remodeling, a process essential to enduring plastic changes in gene expression. Here, we show that repeated social defeat induces changes in BRG1 nuclear distribution. The inactivation of the Brg1/Smarca4 gene within dopamine-innervated regions or the constitutive inactivation of the Brm/Smarca2 gene leads to resilience to repeated social defeat and decreases the behavioral responses to cocaine without impacting midbrain dopamine neurons activity. Within striatal medium spiny neurons Brg1 gene inactivation reduces the expression of stress-and cocaine-induced immediate early genes, increases levels of heterochromatin and at a global scale decreases chromatin accessibility. Altogether these data demonstrate the pivotal function of SWI/SNF complexes in behavioral and transcriptional adaptations to salient environmental challenges

SWI/SNF chromatin remodeler complex within the reward pathway is required for behavioral adaptations to stress

International audienceEnduring behavioral changes upon stress exposure involve changes in gene expression sustained by epigenetic modifications in brain circuits, including the mesocorticolimbic pathway. Brahma (BRM) and Brahma Related Gene 1 (BRG1) are ATPase subunits of the SWI/SNF complexes involved in chromatin remodeling, a process essential to enduring plastic changes in gene expression. Here, we show that in mice, social defeat induces changes in BRG1 nuclear distribution. The inactivation of the Brg1/Smarca4 gene within dopamine-innervated regions or the constitutive inactivation of the Brm/Smarca2 gene leads to resilience to repeated social defeat and decreases the behavioral responses to cocaine without impacting midbrain dopamine neurons activity. Within striatal medium spiny neurons, Brg1 gene inactivation reduces the expression of stress-and cocaine-induced immediate early genes, increases levels of heterochromatin and at a global scale decreases chromatin accessibility. Altogether these data demonstrate the pivotal function of SWI/SNF complexes in behavioral and transcriptional adaptations to salient environmental challenges

Disrupting D1-NMDA or D2-NMDA receptor heteromerization prevents cocaine’s rewarding effects but preserves natural reward processing

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