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The Journal of Neuroscience, September 7, 2005, 25(36):8141-8149; doi:10.1523/JNEUROSCI.2077-05.2005

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Behavioral/Systems/Cognitive
Reduced Cocaine Self-Administration in Muscarinic M₅ Acetylcholine Receptor-Deficient Mice

Morgane Thomsen,^1,2 David P. D. Woldbye,² Gitta Wörtwein,² Anders Fink-Jensen,² Jürgen Wess,³ and S. Barak Caine¹

¹Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478, ²Laboratory of Neuropsychiatry, Rigshospitalet University Hospital and Department of Pharmacology, University of Copenhagen, DK-2100 Copenhagen, Denmark, and ³Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

The reinforcing effects of cocaine have been related to increased extracellular concentrations of dopamine in the ventral striatum. Several studies suggest that M₅ muscarinic receptors facilitate striatal dopamine release. We tested the hypothesis that the reinforcing effects of cocaine are decreased in M₅ receptor-deficient mice using chronic intravenous cocaine self-administration in extensively backcrossed mice. We also assessed whether operant performance generally, rather than cocaine self-administration specifically, was altered in the mutant mice. To this end, we evaluated both food-maintained operant behavior and cocaine self-administration under a fixed ratio 1 and a progressive ratio (PR) schedule of reinforcement. We also evaluated acquisition of self-administration in experimentally naive mice using several doses of cocaine. M₅ receptor deletion decreased self-administration of low to moderate doses of cocaine under a PR schedule of reinforcement and diminished acquisition of self-administration of a low dose in experimentally naive mice. We found no differences between genotypes in food-maintained behavior. The present study extends our previous findings using backcrossed mice and covering various experimental conditions. Our results indicate that M₅ receptor deletion diminished the reinforcing effects of low doses of cocaine and identified specific conditions under which this may be observed.

Key words: muscarinic; M₅; acetylcholine; knock-out; self-administration; cocaine

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Received May 23, 2005; revised July 21, 2005; accepted July 22, 2005.

This article has been cited by other articles:

				M. Thomsen, D. D. Han, H. H. Gu, and S. B. Caine Lack of Cocaine Self-Administration in Mice Expressing a Cocaine-Insensitive Dopamine Transporter J. Pharmacol. Exp. Ther., October 1, 2009; 331(1): 204 - 211. [Abstract] [Full Text] [PDF]

				C. S. McPherson, T. Mantamadiotis, S.-S. Tan, and A. J. Lawrence Deletion of CREB1 from the Dorsal Telencephalon Reduces Motivational Properties of Cocaine Cereb Cortex, August 7, 2009; (2009) bhp159v1. [Abstract] [Full Text] [PDF]

				M. Thomsen, F. S. Hall, G. R. Uhl, and S. B. Caine Dramatically Decreased Cocaine Self-Administration in Dopamine But Not Serotonin Transporter Knock-Out Mice J. Neurosci., January 28, 2009; 29(4): 1087 - 1092. [Abstract] [Full Text] [PDF]

				S. Steidl and J. S. Yeomans M5 Muscarinic Receptor Knockout Mice Show Reduced Morphine-Induced Locomotion but Increased Locomotion after Cholinergic Antagonism in the Ventral Tegmental Area J. Pharmacol. Exp. Ther., January 1, 2009; 328(1): 263 - 275. [Abstract] [Full Text] [PDF]

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