Decreased cocaine self-administration in Kir3 potassium channel subunit knockout mice.
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 ion channels 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 key neuronal 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, Kir3.2 and Kir3.3 knockout mice exhibited dramatically reduced intravenous self-administration of cocaine relative to wild-type mice over a range of cocaine doses. Paradoxically, Kir3.2/3.3 double knockout mice self-administered cocaine at levels significantly higher than either single knockout alone. These findings suggest that Kir3 channels play significant and complex roles in the reinforcing effect of cocaine.
Morgan
Andrew D
AD
Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA.
Carroll
Marilyn E
ME
Loth
Annemarie K
AK
Stoffel
Markus
M
Wickman
Kevin
K
D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000172:deficiency* / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying / Q000172:deficiency* / Q000235:genetics; D012646:Self Administration / Q000523:psychology
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C497072:Kcnj9 protein, mouse; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D003042:Cocaine