In summary, we demonstrate that genetic ablation of Girk1 and Girk2 promotes adaptations in the mesolimbic DA system that facilitate excitatory glutamatergic neurotransmission. The adaptations observed are reminiscent of those reported for synaptic scaling and following drug administration, suggesting that Girk channels may normally serve as a barrier to such adaptations. Accordingly, the regulation of Girk signaling strength, perhaps in VTA DA neurons and/or in neurons that provide input to the VTA, may constitute in part the mechanism by which drugs of abuse evoke adaptations that promote chronic drug intake, or provide a target for therapeutic interventions aimed at preventing such adaptations.
