Bordia_2012_J.Pharmacol.Exp.Ther_342_327

Extensive evidence indicates that varenicline reduces nicotine craving and withdrawal symptoms by modulating dopaminergic function at alpha4beta2* nicotinic acetylcholine receptors (nAChRs) (the asterisk indicates the possible presence of other nicotinic subunits in the receptor complex). More recent data suggest that alpha6beta2* nAChRs also regulate dopamine release and mediate nicotine reinforcement. The present experiments were therefore done to test the effect of varenicline on alpha6beta2* nAChRs and their function, because its interaction with this subtype is currently unclear. Receptor competition studies showed that varenicline inhibited alpha6beta2* nAChR binding (K(i) = 0.12 nM) as potently as alpha4beta2* nAChR binding (K(i) = 0.14 nM) in rat striatal sections and with approximately 20-fold greater affinity than nicotine. Functionally, varenicline was more potent in stimulating alpha6beta2* versus alpha4beta2* nAChR-mediated [(3)H]dopamine release from rat striatal synaptosomes with EC(50) values of 0.007 and 0.086 muM, respectively. However, it acted as a partial agonist on alpha6beta2* and alpha4beta2* nAChR-mediated [(3)H]dopamine release with maximal efficacies of 49 and 24%, respectively, compared with nicotine. We also evaluated varenicline's action in striatum of monkeys, a useful animal model for comparison with humans. Varenicline again potently inhibited monkey striatal alpha6beta2* (K(i) = 0.13 nM) and alpha4beta2* (K(i) = 0.19 nM) nAChRs in competition studies. Functionally, it potently stimulated both alpha6beta2* (EC(50) = 0.014 muM) and alpha4beta2* (EC(50) = 0.029 muM) nAChR-mediated [(3)H]dopamine release from monkey striatal synaptosomes, again acting as a partial agonist relative to nicotine at both subtypes. These data suggest that the ability of varenicline to interact at alpha6beta2* nAChRs may contribute to its efficacy as a smoking cessation aid.