Girk2−/− mice exhibit a basal hyperactivity that was normalized by the D1 DA receptor (D1R) antagonist SCH 23390 (Blednov et al. 2001; Blednov et al. 2002), indicating that Girk2−/− mice exhibit elevated DA signaling. Girk2−/− mice also exhibit enhanced responses to the acute motor-stimulatory effects of cocaine and the D1R partial agonist SKF 38393 (Blednov et al. 2002; Morgan et al. 2003). One interpretation of these data is that Girk2 ablation diminishes inhibitory feedback to VTA DA neurons and/or triggers elevated intrinsic excitability of VTA DA neurons, leading to elevated DA release in the NAcc and striatum. Secondary adaptations, perhaps linked to alterations in excitatory signaling, might also explain the DA-related phenotypes reported in Girk2−/− mice. Indeed, such adaptations are triggered by drugs of abuse and stress, and can promote persistent adaptations in the NAcc that are implicated in behavioral sensitization (Kauer and Malenka 2007; Engblom et al. 2008; Thomas et al. 2008; Zweifel et al. 2008; Heshmati 2009).
