Characterization of GABAergic projection from the ventral tegmental area to the nucleus accumbens: Effects of dopamine and cocaine

Within the mesolimbic dopamine (DA) system, the VTA-to-NAc projection is essential for many emotional and motivational responses, and is often targeted by drugs of abuse to produce cellular and behavioral alterations. Whereas the DAergic component in this projection has been extensively examined for its role in mediating the primary reward effect and reward prediction, this projection also contain a significant GABAergic component and a relatively weak glutamatergic component. These two fast projections are often concurrently activated with the DAergic projection upon incentive stimuli, but their physiological properties and their relationship with the DAergic component have not been well understood. Focusing on this knowledge gap, our present study utilized a multidisciplinary approach combining electrophysiology, genetics/optogenetics, and operant behavioral tests, to characterize VTA-to-NAc GABAergic projection, its interaction with parallel DAergic projection, and its adaptive changes after cocaine exposure. The parallel glutamatergic projection was examined for comparison. Our results showed that VTA-to-NAc GABAergic transmission exhibited relatively high presynaptic release probability and fast-decaying postsynaptic responses. Activation of parallel DAergic projection induced LTD at VTA-to-NAc GABAergic synapses heterosynaptically. After withdrawal from repeated cocaine exposure, we detected several profound alterations at VTA-to-NAc GABAergic synapses, among which the D1-dependent heterosynaptic LTD was abolished. Furthermore, cocaine-induced alterations in GABAergic and glutamatergic transmissions are highly dynamic, critically depending on cocaine procedures and drug withdrawal periods. These results reveal that GABAergic and glutamatergic projections exert direct inhibitory and excitatory effects on NAc principal neurons, and the shifted inhibitory-excitatory balance in NAc neurons may contribute to the shifted functional output of the NAc. Moreover, given the prominent regulatory role of DA in emotional and motivational response, loss of DA-dependent heterosynaptic plasticity at VTA-to-NAc GABAergic synapses during cocaine withdrawal echoes several withdrawal symptoms such as rigid emotional state favorable to drug taking, reduced responses to non-drug-related emotional stimuli, and persistent hypoactivity of the NAc. The novel roles of VTA-to-NAc GABAergic projection demonstrated in the present study may pave the road for future studies to understand the circuitry-based mechanisms of physiological and pathophysiological emotional and motivational responses