Reduced GABA-B/GIRK-mediated regulation of the VTA following a single exposure to cocaine

In this paper, Arora and colleagues expand on their previous work on GIRK channels in the ventral tegmental area (VTA) presenting evidence that a single exposure to cocaine reduces inhibitory GABAergic transmission to dopamine (DA) neurons in the ventral tegmental area. Mice receiving i.p. injections of cocaine saw a short lived (1-5 days) decrease in GABAb mediated G-protein coupled inwardly-rectifying potassium (GIRK) currents in DA neurons in the VTA. This decrease parallels an NMDA-mediated increase in the frequency of glutamatergic neurotransmission. Chronic cocaine injections had no additional effects beyond those seen with single injections. Though they found no change in mRNA levels for GABAb receptors, GIRK channels, or RGS-2 (a G-protein regulator), immunoelectron microscopy indicated a decrease in levels of GIRK channels in the plasma membrane of the dendrites of VTA DA neurons. The cocaine-mediated decrease in GIRK currents was abolished in the presence of D2/3R antagonist sulpiride, but not in the presence of D1/5 antagonist SCH23390, indicating a link between D2/3 receptor activation and GIRK activity. Interestingly, the addition of quinpirole, a D2/3 agonist, elicited similar GIRK currents, though they were smaller than those mediated by GABAb receptors. Similarly, acute injections of cocaine significantly diminished quinpirole-evoked currents.