The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens.
Mol Psychiatry. 2015-08-04; 20(11): 1448-1459
DOI: 10.1038/mp.2015.104
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1. Mol Psychiatry. 2015 Nov;20(11):1448-59. doi: 10.1038/mp.2015.104. Epub 2015 Aug
4.
The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and
glutamate signaling in the nucleus accumbens.
Sakae DY(1)(2)(3)(4), Marti F(1)(2)(3)(4), Lecca S(1)(5)(6), Vorspan
F(7)(8)(9)(10), Martín-García E(11), Morel LJ(1)(2)(3)(4), Henrion
A(7)(10)(12)(13), Gutiérrez-Cuesta J(11), Besnard A(1)(2)(3), Heck N(1)(2)(3),
Herzog E(1)(2)(3), Bolte S(14), Prado VF(15), Prado MA(15), Bellivier
F(7)(8)(9)(10), Eap CB(16)(17), Crettol S(16), Vanhoutte P(1)(2)(3), Caboche
J(1)(2)(3), Gratton A(4), Moquin L(4), Giros B(1)(2)(3)(4)(7), Maldonado R(11),
Daumas S(1)(2)(3), Mameli M(1)(5)(6), Jamain S(7)(10)(12)(13), El Mestikawy
S(1)(2)(3)(4)(7).
Author information:
(1)Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Paris 06,
Institut de Biologie Paris Seine (IBPS), UM119 Neuroscience Paris Seine, Paris,
France.
(2)Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S
1130, Neuroscience Paris Seine, Paris, France.
(3)Centre National de la Recherche Scientifique (CNRS) UMR 8246, Neuroscience
Paris Seine, Paris, France.
(4)Department of Psychiatry, Douglas Hospital Research Center, McGill University,
Verdun, QC, Canada.
(5)Institut du Fer à Moulin, Paris, France.
(6)Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 839,
Paris, France.
(7)Fondation FondaMental, Créteil, France.
(8)Institut National de la Santé et de la Recherche Médicale (INSERM), U705,
Centre National de la Recherche Scientifique (CNRS) UMR 8206, Université Paris
Descartes, Université Denis Diderot, PRES Sorbonne Paris Cité, Paris, France.
(9)Assistance Publique-Hôpitaux de Paris, GH Saint Louis-Lariboisière-F Widal,
Service de Psychiatrie, Paris, France.
(10)Institut National de la Santé et de la Recherche Médicale (INSERM U955),
Psychiatrie Translationnelle, Créteil, France.
(11)Departament de Ciencies Experimentals i de la Salut, Universitat Pompeu
Fabra, PRBB, Barcelona, Spain.
(12)Université Paris Est, Faculté de Médecine, Créteil, France.
(13)Assistance Publique-Hôpitaux de Paris, Hôpital H. Mondor-A Chenevier, Pôle de
Psychiatrie, Créteil, France.
(14)Cellular Imaging Facility, Institut de Biologie Paris Seine (IBPS), Sorbonne
Universités, Université Pierre et Marie Curie (UPMC), Paris, France.
(15)Department of Anatomy and Cell Biology and Department of Physiology and
Pharmacology, Robarts Research Institute, The University of Western Ontario,
London, ON, Canada.
(16)Unit of Pharmacogenetics and Clinical Psychopharmacology, Department of
Psychiatry, Centre for Psychiatric Neuroscience, Lausanne University Hospital,
Hospital of Cery, Prilly, Switzerland.
(17)Department of Pharmaceutical Sciences, School of Pharmacy, University of
Geneva, University of Lausanne, Geneva, Switzerland.
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.
DOI: 10.1038/mp.2015.104
PMID: 26239290 [Indexed for MEDLINE]