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

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$\alpha4$nicotinic subunits containing a single point mutation,$Leu^{9'} \rightarrow Ala^{9'}$in the pore-forming M2 domain,...

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Published in:Science (American Association for the Advancement of Science) 2004-11, Vol.306 (5698), p.1029-1032
Main Authors: Tapper, Andrew R., McKinney, Sheri L., Nashmi, Raad, Schwarz, Johannes, Deshpande, Purnima, Labarca, Cesar, Whiteaker, Paul, Marks, Michael J., Collins, Allan C., Lester, Henry A.
Format: Article
Language:English
Subjects:
Addiction
Biological and medical sciences
Fundamental and applied biological sciences. Psychology
Intraperitoneal injections
Mice
Midbrain
Neurons
Nicotine
Nicotine dependence
Nicotinic antagonists
Nicotinic receptors
Physiological aspects
Receptors
Sensitization
Smoking
Up regulation
Vertebrates: nervous system and sense organs
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Summary: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$\alpha4$nicotinic subunits containing a single point mutation,$Leu^{9'} \rightarrow Ala^{9'}$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.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1099420