Release of the neurotransmitter dopamine in the mesolimbic system of the brain mediates the reinforcing properties of several drugs of abuse, including nicotine(1). Here we investigate the contribution of the high-affinity neuronal nicotinic acetylcholine receptor(2) to the effects of nicotine on the mesolimbic dopamine system in mice lacking the beta 2 subunit of this receptor(3). We found that nicotine stimulates dopamine release in the ventral striatum of wild-type mice but not in the ventral striatum of beta 2-mutant mice. Using patch-clamp recording, we show that mesencephalic dopaminergic neurons from mice without the beta 2 subunit no longer respond to nicotine, and that self-administration of nicotine is attenuated in these mutant mice. Our results strongly support the idea that the beta 2-containing neuronal nicotinic acetycholine receptor is involv ed in mediating the reinforcing properties of nicotine.