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)' --> Ala(9)' in the pore-forming M2 domain, rendering alpha4* receptors hypersensitive to nicotine. Selective activation of alpha4* 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 alpha4* receptors is sufficient for nicotine-induced reward, tolerance, and sensitization.