Dopamine-related drugs act presynaptically to potentiate GABAA receptor currents in VTA dopamine neurons

Electrical activity of ventral tegmental area (VTA) dopamine (DA) neurons is immediately inhibited following in vivo administration of cocaine and other DA-related drugs. While various forms of synaptic modulation were demonstrated in the VTA following exposure to DA-related drugs, comprehensive understanding of their ability to inhibit the activity of DA neurons, however, is still lacking. In this study, using whole-cell patch-clamp recordings from rat brain slices, a novel form of synaptic modulation induced by DA-related drugs was isolated. DA exposure was shown to cause potentiation of γ-amino-butyric acid (GABA) receptor type A (GABAAR)-mediated evoked inhibitory postsynaptic currents (eIPSCs), recorded from VTA DA neurons, under conditions of potassium channels blockade. The potentiation of these eIPSCs lasted for more than twenty minutes, could be mimicked by activation of D2-like but not D1-like DA receptors, and was accompanied by an increase in the frequency of GABAAR-mediated spontaneous miniature inhibitory postsynaptic currents (mIPSCs). Furthermore, exposure to inhibitors of DA transporter (DAT) led to potentiation of GABAA currents in a manner similar to the DA-mediated potentiation. Finally, a prolonged presence of l-NAME, an inhibitor of nitric-oxide (NO) signaling was found to conceal the potentiation of GABAA currents induced by the DA-related drugs. Taken together, this study demonstrates a new modulatory form of VTA GABAA neurotransmission mediated by DA-related drugs. These results also suggest better understanding of the initial inhibitory action of DA-related drugs on the activity of DA neurons in the VTA.

► DA causes potentiation of GABAA receptor IPSCs recorded from VTA DA neurons.
► DA-induced potentiation of IPSCs could be mimicked by activation of D2-like but not D1-like receptors.
► DA-induced potentiation of IPSCs could be mimicked by inhibitors of DA transporter.
► DA-induced potentiation of IPSCs was accompanied by an increase in the frequency of GABAAR-mediated mIPSCs.
► Blockade of nitric-oxide (NO) signaling mimicked DA-induced potentiation of IPSCs.