%0 Journal Article %A Tanuja Bordia %A Maya Hrachova %A Matthew Chin %A J. Michael McIntosh %A Maryka Quik %T Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum %D 2012 %R 10.1124/jpet.112.194852 %J Journal of Pharmacology and Experimental Therapeutics %P 327-334 %V 342 %N 2 %X Extensive evidence indicates that varenicline reduces nicotine craving and withdrawal symptoms by modulating dopaminergic function at α4β2* nicotinic acetylcholine receptors (nAChRs) (the asterisk indicates the possible presence of other nicotinic subunits in the receptor complex). More recent data suggest that α6β2* nAChRs also regulate dopamine release and mediate nicotine reinforcement. The present experiments were therefore done to test the effect of varenicline on α6β2* nAChRs and their function, because its interaction with this subtype is currently unclear. Receptor competition studies showed that varenicline inhibited α6β2* nAChR binding (Ki = 0.12 nM) as potently as α4β2* nAChR binding (Ki = 0.14 nM) in rat striatal sections and with ∼20-fold greater affinity than nicotine. Functionally, varenicline was more potent in stimulating α6β2* versus α4β2* nAChR-mediated [3H]dopamine release from rat striatal synaptosomes with EC50 values of 0.007 and 0.086 μM, respectively. However, it acted as a partial agonist on α6β2* and α4β2* nAChR-mediated [3H]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 α6β2* (Ki = 0.13 nM) and α4β2* (Ki = 0.19 nM) nAChRs in competition studies. Functionally, it potently stimulated both α6β2* (EC50 = 0.014 μM) and α4β2* (EC50 = 0.029 μM) nAChR-mediated [3H]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 α6β2* nAChRs may contribute to its efficacy as a smoking cessation aid. %U https://jpet.aspetjournals.org/content/jpet/342/2/327.full.pdf