Nicotine Activation of α4* Receptors: Sufficient for Reward, Tolerance, and Sensitization

American Association for the Advancement of Science (AAAS) - Tập 306 Số 5698 - Trang 1029-1032 - 2004
Andrew R. Tapper1,2,3, Sheri McKinney1,2,3, Raad Nashmi1,2,3, Johannes Schwarz1,2,3, Purnima Deshpande1,2,3, Cesar Labarca1,2,3, Paul Whiteaker1,3, Michael J. Marks1,3, Allan C. Collins1,3, Henry A. Lester1,2,3
1Department of Neurology, University of Leipzig, 04103 Leipzig, Germany
2Division of Biology, California Institute of Technology, Pasadena, CA 91125 USA
3Institute of Behavioral Genetics, University of Colorado, Boulder, CO 80309, USA.

Tóm tắt

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 α4 nicotinic subunits containing a single point mutation, Leu 9′ → Ala 9′ in the pore-forming M2 domain, rendering α4* receptors hypersensitive to nicotine. Selective activation of α4* 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 α4* receptors is sufficient for nicotine-induced reward, tolerance, and sensitization.

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This research was supported by the California Tobacco-Related Disease Research Project (grant 12RT-0245 and fellowship 10FT-0174 to R.N.) by the NIH (grants DA-3194 and DA-15663 at Boulder NS-11756 and MH-49716 at Caltech and National Research Service Award to A.R.T.) and by the W. M. Keck and Plum Foundations. We thank C. Fonck B. Cohen S. Kwoh N. Rodrigues-Pinguet S. Grady J. Wehner and S. Malin for access to unpublished work.

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American Association for the Advancement of Science (AAAS)

Tập 306 Số 5698

1029-1032

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