title: Circuit specificity in the inhibitory architecture of the VTA regulates cocaine-induced behavior.
abstract: Afferent inputs to the ventral tegmental area (VTA) control reward-related behaviors through regulation of dopamine neuron activity. The nucleus accumbens (NAc) provides one of the most prominent projections to the VTA; however, recent studies have provided conflicting evidence regarding the function of these inhibitory inputs. Using optogenetics, cell-specific ablation, whole cell patch-clamp and immuno-electron microscopy, we found that NAc inputs synapsed directly onto dopamine neurons, preferentially activating GABABreceptors. GABAergic inputs from the NAc and local VTA GABA neurons were differentially modulated and activated separate receptor populations in dopamine neurons. Genetic deletion of GABABreceptors from dopamine neurons in adult mice did not affect general or morphine-induced locomotor activity, but markedly increased cocaine-induced locomotion. Collectively, our findings demonstrate notable selectivity in the inhibitory architecture of the VTA and suggest that long-range GABAergic inputs to dopamine neurons fundamentally regulate behavioral responses to cocaine.
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, US National Institutes of Health, Baltimore, Maryland, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Edwards
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, US National Institutes of Health, Baltimore, Maryland, USA.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Tejeda
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, US National Institutes of Health, Baltimore, Maryland, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Pignatelli
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, US National Institutes of Health, Baltimore, Maryland, USA.
authors.forename: Shiliang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, US National Institutes of Health, Baltimore, Maryland, USA.
authors.forename: Ross A
authors.initials: RA
authors.lastname: McDevitt
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, US National Institutes of Health, Baltimore, Maryland, USA.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York, USA.
authors.forename: Caroline E
authors.identifier: http://orcid.org/0000-0002-5856-6387
authors.initials: CE
authors.lastname: Bass
authors.affiliation: Department of Biomedicine, Pharmazentrum, University of Basel, Basel, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, US National Institutes of Health, Baltimore, Maryland, USA.
authors.forename: Marisela
authors.initials: M
authors.lastname: Morales
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, US National Institutes of Health, Baltimore, Maryland, USA.|Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Antonello
authors.initials: A
authors.lastname: Bonci
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000502:physiology / Q000648:ultrastructure; D005260:Female; D055785:Gene Knockdown Techniques; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009433:Neural Inhibition / Q000502:physiology*; D009714:Nucleus Accumbens / Q000502:physiology*; D043682:Receptor, Adenosine A1 / Q000502:physiology; D011963:Receptors, GABA-A / Q000502:physiology; D018080:Receptors, GABA-B / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012201:Reward; D009435:Synaptic Transmission / Q000502:physiology; D017557:Ventral Tegmental Area / Q000502:physiology* / Q000648:ultrastructure
chemical_list: D043682:Receptor, Adenosine A1; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D009020:Morphine; D003042:Cocaine