The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens.

TitleThe absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens.
Publication TypeJournal Article
Year of Publication2015
AuthorsSakae DY, Marti F, Lecca S, Vorspan F, Martín-García E, Morel LJ, Henrion A, Gutiérrez-Cuesta J, Besnard A, Heck N, Herzog E, Bolte S, Prado VF, Prado MAM, Bellivier F, Eap CB, Crettol S, Vanhoutte P, Caboche J, Gratton A, Moquin L, Giros B, Maldonado R, Daumas S, Mameli M, Jamain S, Mestikawy SEl
JournalMol Psychiatry
Volume20
Issue11
Pagination1448-59
Date Published2015 Nov
ISSN1476-5578
Abstract

Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3(-/-) mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3(-/-) mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse.

DOI10.1038/mp.2015.104
Alternate JournalMol. Psychiatry
PubMed ID26239290

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