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 a4 nicotinic subunits containing a single point mutation, Leu9' --> Ala9' in the pore-forming M2 domain, rendering a4* receptors hypersensitive to nicotine. Selective activation of a4* 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 a4* receptors is sufficient for nicotine-induced reward, tolerance, and sensitization.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alkaloids / metabolism
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Animals
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Azocines / metabolism
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Brain / drug effects
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Brain / metabolism
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Bridged Bicyclo Compounds, Heterocyclic / metabolism
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Calcium / metabolism
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Cells, Cultured
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Drug Tolerance*
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Leucine
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Mice
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Mice, Inbred C57BL
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Motor Activity / drug effects
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Neurons / metabolism
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Nicotine / pharmacology*
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Point Mutation
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Pyridines / metabolism
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Quinolizines / metabolism
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Receptors, Nicotinic / genetics
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Receptors, Nicotinic / physiology*
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Reward*
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Serine
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Tobacco Use Disorder / metabolism*
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Up-Regulation
Substances
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Alkaloids
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Azocines
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Bridged Bicyclo Compounds, Heterocyclic
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Pyridines
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Quinolizines
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Receptors, Nicotinic
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nicotinic acetylcholine receptor alpha4 subunit
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Serine
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cytisine
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Nicotine
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Leucine
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epibatidine
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Calcium