In addition to potentiating DA signaling within the NAcc, cocaine also triggers “long-loop” and auto-inhibitory feedback to the VTA mediated by GABAB (GABABR) and D2 DA (D2R) receptors, respectively. G protein-gated inwardly-rectifying K+ (Girk/KIR3) channels are expressed in VTA DA neurons and mediate the postsynaptic inhibitory effect of GABABR and D2R activation (Beckstead et al. 2004; Cruz et al. 2004; Labouebe et al. 2007). The prototypical neuronal Girk channel is a heterotetramer formed by Girk1 and Girk2 subunits (Karschin et al. 1996; Liao et al. 1996; Luscher et al. 1997; Koyrakh et al. 2005). Midbrain DA neurons of the VTA and substantia nigra (SN), however, do not express Girk1 (Karschin et al. 1996; Inanobe et al. 1999; Cruz et al. 2004; Labouebe et al. 2007). Thus, genetic ablation of Girk2 correlates with blunted GABABR- and D2R-dependent postsynaptic inhibition in VTA and SN DA neurons, whereas loss of Girk1 has no effect (Beckstead et al. 2004; Cruz et al. 2004; Koyrakh et al. 2005; Labouebe et al. 2007).
