Abstract:Elevated dopamine (DA) levels in the reward system underlie various drug-related behaviors, including addiction. As a major DA source in the reward system, the ventral tegmental area (VTA) is highly regulated by GABAergic inputs projected from different brain regions. It was previously shown that cocaine exposure reduces GABAA-mediated inhibitory postsynaptic currents (IPSCs) in VTA DA neurons; however, the specific GABAergic input underlying this inhibitory effect remains unknown. Here, using optogenetics, we separately activate and characterize different GABAergic afferents innervating the VTA, focusing on the rostromedial tegmental nucleus (RMTg) and the nucleus accumbens (NAc). GABAA-mediated IPSCs were recorded from VTA DA neurons, and the effect of DA-induced inhibition was measured in an afferent-specific manner. In addition, to examine the effect of enhanced GABAergic tone on the rewarding properties of cocaine, we exogenously activated the different GABAergic inputs during the acquisition phase of cocaine conditioned place preference (CPP). We found that acute cocaine exposure strongly attenuates GABAA-mediated IPSCs in VTA DA neurons from both inhibitory sources. Furthermore, exogenous light activation of both RMTg and NAc afferents in the VTA during the acquisition of cocaine-CPP significantly reduced the rewarding properties of cocaine. This behavioral observation was correlated with the reduction in the neuronal activity of VTA DA neurons as measured by the expression of c-fos. Together, these results emphasize the critical role of these GABAergic inputs to the VTA in modulating and potentially interrupting cocaine reward.