Multiple G protein-linked neurotransmitter Systems have been implicated in the behavioral effects of cocaine. While actions of certain neurotransmitter receptor subtypes and transporters have been identified, the role of individual G protein-regulated enzymes and ionchannels in the effects of cocaine remains unclear. Here, we assessed the contribution of G protein-gated, inwardly rectifying potassium(Kir3/GIRK) channels to the locomotor-stimulatory and reinforcing effects of cocaine using knockout mice lacking one or both of the keyneuronal channel subunits, Kir3.2 and Kir3.3. Cocaine-stimulated increases in horizontal locomotor activity in wild-type, Kir3.2 knockout, Kir3.3 knockout, and Kir3.2/3.3 double knockout mice, with only minor differences observed between the mouse lines. In contrast, Kir3.2and Kir3.3 knockout mice exhibited dramatically reduced intravenous self-administration of cocaine relative to wild-type mice over arange of cocaine doses. Paradoxically, Kir3.2/3.3 double knockout mice self-administered cocaine at levels significantly higher than eithersingle knockout alone. These findings suggest that Kir3 channels play significant and complex roles in the reinforcing effect of cocaine.
Bibliographical noteFunding Information:
We thank Maria Roman, and Stephanie Cintora for assistance with mouse genotyping, and Megan Roth and Erin Larson for careful reading of the manuscript. This work was supported by NIH Grants T32 DA07097 (ADM), RO1 DA03240, K05 DA15267 (MEC), RO1 MH61933 (KW), and a PhRMA Foundation Research Starter Award (KW).
- Locomotor activity