Baseline expression of alpha4beta2* nicotinic acetylcholine receptors predicts motivation to self-administer nicotine.

BACKGROUND: Marked interindividual differences in vulnerability to nicotine dependence exist, but factors underlying such differences are not well understood. The midbrain alpha4beta2* subtype of nicotinic acetylcholine receptors (nAChRs) has been implicated in mediation of the reinforcing effects of nicotine responsible for dependence. However, no study has been performed evaluating the impact of interindividual differences in midbrain nAChR levels on motivation to self-administer nicotine. METHODS: Baseline levels of alpha4beta2* nAChRs were measured using 2-[(18)F]fluoro-A-85380 (2-FA) and positron emission tomography (PET) in five squirrel monkeys. Motivation to self-administer nicotine (number of lever presses) was subsequently measured using a progressive-ratio (PR) schedule of reinforcement. RESULTS: Greater motivation to self-administer nicotine was associated with lower levels of midbrain nAChRs. CONCLUSIONS: The results suggest that level of expression of nAChRs is a contributing factor in the development of nicotine dependence. Similarly, it has been previously shown that low levels of dopamine D(2) receptors (DRD2) are associated with a higher preference for psychostimulant use in humans and nonhuman primates. Together, results from these PET studies of dopaminergic and nicotinic cholinergic transmission suggest that an inverse relationship between the availability of receptors that mediate reinforcement and the motivation to take drugs exists across different neurotransmitter systems.