Circuit Specificity in the Inhibitory Architecture of the VTA Regulates Behavioral Responses to Cocaine

National Institute On Drug Abuse

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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 functional role of these inhibitory inputs. Using optogenetics, cell-specific ablation, whole cell patch-clamp, and immuno-electron microscopy, we show that NAc inputs synapse directly onto dopamine neurons, preferentially activating GABAB receptors. We demonstrate that GABAergic inputs from the NAc and local VTA GABA neurons are differentially modulated and activate separate receptor populations within dopamine neurons. Genetic deletion of GABAB receptors from dopamine neurons in adult mice did not affect general or morphine-induced locomotor activity, but profoundly increased cocaine-induced locomotion. Collectively, our findings demonstrate remarkable selectivity in the inhibitory architecture of the VTA and suggest that long-range GABAergic inputs to dopamine neurons fundamentally regulate behavioral responses to cocaine.