SAMENTA - Santé Mentale - Addictions

VGLUT3, cholinergic striatal interneurons and addiction – COCACh

Submission summary

Addiction is a compulsive pattern of drug-seeking/drug-taking behavior with reoccurring episode of abstinence and relapse, and a loss of control despite negative consequences. Addiction is primarily a disease of the brain reward system. In order to improve treatment of addictive disorders, a clear understanding of reward circuits is needed. The neurobiology of motivated behavior involves numerous intricate circuits and neurotransmitters. Dysregulation of numerous neurotransmitters is involved in the pathophysiology of addictions. Dopaminergic transmission is currently viewed as central in reward and addiction. Given their regulatory properties in basal ganglia, cholinergic interneurons (TANs) from the nucleus accumbens (NAc) have also been the focus of many studies. However, the role of TANs in addiction remains largely elusive. Previous experiments using immunotoxins to ablate TANs provided evidence that these neurons were involved in rewarding properties of cocaine. It has long been assumed that these functions of TANs were performed by ACh signaling. Recently, a mouse line with selective elimination of the vesicular acetylcholine transporter (VAChT) from TANs was developed. Because VAChT is essential for ACh vesicular storage, these mutant mice no longer release ACh in the Nac. Surprisingly, these mutants mice showed minimal alteration in behavioral responses to cocaine suggesting that i) ACh from TANs is not sufficient to produce reward modulation and that ii) TANs use another neurotransmitter to signal.
Eight years ago, we made the observation that TANs express an atypical vesicular glutamate transporter (named VGLUT3) in their terminals. Our results as well as data from the literature clearly established that VGLUT3 i) increases cholinergic tone and ii) confers TANs the ability to release glutamate. Additionally, we observed that mice null for the vglut3 gene (VGLUT3-KO) are more responsive to cocaine than wild-type littermates, phenocopying mice with ablation of TANs. We have obtained preliminary results that led us to two major hypotheses:
i) TANs use two distinct neurotransmitters to differentially regulate striatal physiology. This represents a major change in how we understand neuronal communication.
ii) TANs modulate reward behaviors through glutamate release and not through ACh.
To validate these hypotheses we propose to address the following questions in animal models:
i) Does VGLUT3 impact on cocaine-induced phenotypes (locomotor activity, conditioned place preference, sensitization and self-administration) or only on part of them? ii) Does VGLUT3-dependent glutamate modify dopamine levels in the NAc and on neuroplasticity of the reward circuits (signaling cascades, dendritic spine formation, cortico-accumbens plasticity)?
To perform these tasks we will use a multidisciplinary approach to bridge the gap between VGLUT3 and reward behaviors. VGLUT3-constitutive or -conditional KO, as well as knock-down will be investigated by i) biochemical, ii) electrophysiological and iii) behavioral methods.
In addition, if our working hypotheses are correct we surmised that VGLUT3 could be a vulnerability factor to addiction in humans. Consequently, we will screen for mutations of SLC17A8, the gene encoding VGLUT3, in a cohort of patients with severe addiction to cocaine. Preliminary data already revealed VGLUT3 mutated isoforms in patients with cocaine abuse. Their phenotype will be further characterized with already collected data (lifetime addictive history, psychiatric disorders including ADHD, anxiety disorders, personality traits) and neuropsychological tasks (impulsivity, anxiety and drug craving measurement with stress related cues).
This combination of experimental approaches is expected to increase our understanding of molecular mechanisms underlying reward and, on the long range, to identify a genetic vulnerability factor and a novel target for the treatment of addictions.

Project coordination

Salah EL MESTIKAWY (Pathophysiologie des maladies du SNC, INSERM U952, CNRS UMR7224 Université Pierre et Marie Curie)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CNRS UMR 7224 INS Pathophysiologie des maladies du SNC, INSERM U952, CNRS UMR7224 Université Pierre et Marie Curie
INSERM U955, EQ15 Inserm U955, Psychiatrie Génétique
INSERM U705 Neuropsychopharmacologie des Addictions, INSERM U705, CNRS UMR8206, Universités Paris Descartes et Paris Diderot, PRES Sorbonne Paris Cité

Help of the ANR 370,258 euros
Beginning and duration of the scientific project: December 2013 - 36 Months

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