title: Varenicline is a potent partial agonist at α6β2* nicotinic acetylcholine receptors in rat and monkey striatum.
abstract: 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 (K(i) = 0.12 nM) as potently as α4β2* nAChR binding (K(i) = 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 [(3)H]dopamine release from rat striatal synaptosomes with EC(50) values of 0.007 and 0.086 μM, respectively. However, it acted as a partial agonist on α6β2* and α4β2* 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 α6β2* (K(i) = 0.13 nM) and α4β2* (K(i) = 0.19 nM) nAChRs in competition studies. Functionally, it potently stimulated both α6β2* (EC(50) = 0.014 μM) and α4β2* (EC(50) = 0.029 μM) 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 α6β2* nAChRs may contribute to its efficacy as a smoking cessation aid.
authors.affiliation: Center for Health Sciences, SRI International, 333 Ravenswood Ave, Menlo Park, CA 94025, USA.
authors.forename: Tanuja
authors.initials: T
authors.lastname: Bordia
authors.forename: Maya
authors.initials: M
authors.lastname: Hrachova
authors.forename: Matthew
authors.initials: M
authors.lastname: Chin
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.forename: Maryka
authors.initials: M
authors.lastname: Quik
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D008297:Male; D009538:Nicotine / Q000378:metabolism; D011485:Protein Binding; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012453:Saimiri; D016540:Smoking Cessation; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D000068580:Varenicline
chemical_list: D001552:Benzazepines; D011810:Quinoxalines; D011978:Receptors, Nicotinic; C559463:alpha6beta2 nicotinic acetylcholine receptor; C403531:nicotinic receptor alpha4beta2; D009538:Nicotine; D004298:Dopamine; D000068580:Varenicline