VTA GABA Cell Bipotential Induction of iLTP or iLTD Synaptic Plasticity is Input Selective, where iLTD is Uniquely Eliminated by Cocaine.

Abstract

The ventral tegmental area (VTA) is a key reward circuit hub, implicated in drug seeking and addictive behaviors. The VTA contains dopaminergic and GABAergic neurons that both play roles in reward prediction, aversion, motivated reward behavior, etc. Synaptic plasticity, including VTA excitatory and inhibitory long-term potentiation (LTP/iLTP) and long-term depression (LTD/iLTD), are fundamentally involved in processing reward learning and memory, which is maladaptively altered by abused drugs mediating dependence induction. This report extends our prior research of the understudied VTA GABA cells and the rationale for their bipotential plasticity (iLTP or iLTD) capacity by optogenetic circuit level examination of their unique GABAergic inputs. In addition, we examine potential cocaine impact on both plasticity forms. Optogenetic activation of either lateral hypothalamus or rostromedial tegmental nucleus induced iLTP in VTA GABA cells, while optogenetic activation of local VTA GABAergic inputs induced iLTD. This suggests expression of bipotential plasticity is input specific, and highlights implications for each type of plasticity on reward signaling. Drug of abuse cocaine eliminated iLTD while sparing iLTP, suggesting selective impairment of local GABA signaling to VTA GABA cells by cocaine versus projection GABA signaling. This emphasizes potential differential VTA GABA cell plasticity in reward processing and the need to further examine cocaine impact on inhibitory signaling in addition to known impact on the dopaminergic system. By elucidating the circuit-dependence of plasticity type in VTA GABA cells and drug-induced impact, our research could potentially identify additional targets for therapeutic intervention of drug dependence via the GABAergic system.