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, 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.