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Science 306 (5698): 1029-1032

Copyright © 2004 by the American Association for the Advancement of Science

Nicotine Activation of {alpha}4* Receptors: Sufficient for Reward, Tolerance, and Sensitization

Andrew R. Tapper,1 Sheri L. McKinney,1 Raad Nashmi,1 Johannes Schwarz,1,2 Purnima Deshpande,1 Cesar Labarca,1 Paul Whiteaker,3 Michael J. Marks,3 Allan C. Collins,3 Henry A. Lester1*

Abstract: The identity of nicotinic receptor subtypes sufficient to elicit both the acute and chronic effects of nicotine dependence is unknown. We engineered mutant mice with {alpha}4 nicotinic subunits containing a single point mutation, Leu9' -> Ala9' in the pore-forming M2 domain, rendering {alpha}4* receptors hypersensitive to nicotine. Selective activation of {alpha}4* nicotinic acetylcholine receptors with low doses of agonist recapitulates nicotine effects thought to be important in dependence, including reinforcement in response to acute nicotine administration, as well as tolerance and sensitization elicited by chronic nicotine administration. These data indicate that activation of {alpha}4* receptors is sufficient for nicotine-induced reward, tolerance, and sensitization.

1 Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
2 Department of Neurology, University of Leipzig, 04103 Leipzig, Germany.
3 Institute of Behavioral Genetics, University of Colorado, Boulder, CO 80309, USA.

* To whom correspondence should be addressed. E-mail: lester{at}caltech.edu

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