Chronic elevation of glutamatergic signaling in VTA DA neurons promotes persistent adaptations in glutamatergic signaling in the NAcc (Mameli et al. 2009). These adaptations are thought to underlie drug-seeking behavior and behavioral sensitization (Kalivas 2004; Self 2004). Interestingly, Girk1−/− and Girk2−/− mice show enhanced responses to acute cocaine administration, and the NAcc adaptations seen in Girk1−/− and Girk2−/− mice, including increased synapse density and elevated excitatory signaling, overlap with those in animals treated chronically with psychostimulants. Enhanced excitatory signaling in the NAcc, however, is thought to be a response to cocaine withdrawal rather than a consequence of repeated cocaine exposure (Kourrich et al. 2007). As such, adaptations in drug-naïve, constitutive Girk1−/− and Girk2−/− mice may be distinct from those linked to drug exposure.
