Long-loop (GABABR-dependent) and autocrine (D2R-dependent) inhibitory feedback to VTA DA neurons is triggered by cocaine-induced increases in DA levels in the NAcc and VTA, respectively, and lead to tempered VTA DA neuron output and motor stimulation (Wolf et al. 1978; Einhorn et al. 1988; Napier and Potter 1989; Chen and Reith 1994). Simultaneous pharmacological inhibition of both feedback pathways evokes hyperactivity and exaggerated responses to psychostimulants, including cocaine (Steketee et al. 1991, 1992; Narayanan et al. 1996). Since Girk channels mediate the postsynaptic inhibitory effects linked to GABABR and D2R activation, Girk ablation in midbrain DA neurons should promote hyperactivity and exaggerated motor-stimulatory responses to cocaine due to the weakening of these inhibitory feedback mechanisms. Moreover, given that the Girk channel in midbrain DA neurons contains Girk2 but not Girk1, one would predict that hyperactivity and enhanced responses to cocaine would be seen in Girk2−/− but not Girk1−/− mice. To the contrary, Girk1−/− and Girk2−/− mice showed comparable baseline hyperactivities and enhanced responses to acute cocaine. Thus, the loss of inhibitory feedback to VTA DA neurons cannot explain the DA-dependent phenotypes manifest in Girk2−/− mice.
