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Articles and Reports

Journal Article of Cocaine Effects on Animals by M. Caroll, A. Morgan, A. Loth, M. Stoffel, and K. Wickman

Neuropsychopharmacology (2003) 28, 932–938, advance online publication, 5 March 2003; doi:10.1038/sj.npp.1300100

Decreased Cocaine Self-Administration in Kir Potassium Channel Subunit Knockout Mice
Andrew D Morgan1, Marilyn E Carroll, Annemarie K Loth, Markus Stoffel and Kevin Wickman

1. Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA
2. Laboratory of Metabolic Diseases, The Rockefeller University, New York, NY, USA
3. Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA

Correspondence: Dr K Wickman, Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA. Tel: +1 612 624 5966; Fax: +1 612 625 8408; E-mail: wickm002@tc.umn.edu

Received 4 June 2002; Revised 16 October 2002; Accepted 18 October 2002; Published online 5 March 2003.

Abstract
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.

Keywords:
cocaine, locomotor activity, mouse, self-administration, potassium

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See University of Minnesota for additional information.

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