New insights on the effects of varenicline on nicotine reward, withdrawal and hyperalgesia in mice

Varenicline, a partial agonist for alpha 4 beta 42* nicotinic acetylcholine receptors (nAChRs) and a full agonist for alpha 3 beta 4 and alpha 7 nAChRs, is approved for smoking cessation treatment. Although, partial agonism at alpha 4 beta 2* nAChRs is believed to be the mechanism underlying the effects of varenicline on nicotine reward, the contribution of other nicotinic subtypes to varenicline's effects on nicotine reward is currently unknown. Therefore, we examined the role of alpha 5 and alpha 7 nAChR subunits in the effects of varenicline on nicotine reward using the conditioned place preference (CPP) test in mice. Moreover, the effects of varenicline on nicotine withdrawal-induced hyperalgesia and aversion are unknown. We also examined the reversal of nicotine withdrawal in mouse models of dependence by varenicline. Varenicline dose-dependently blocked the development and expression of nicotine reward in the CPP test. The blockade of nicotine reward by varenicline (0.1 mg/kg) was preserved in alpha 7 knockout mice but reduced in alpha 5 knockout mice. Administration of varenicline at high dose of 2.5 mg/kg resulted in a place aversion that was dependent on alpha 5 nAChRs but not beta 2 nAChRs. Furthermore, varenicline (0.1 and 0.5 mg/kg) reversed nicotine withdrawal signs such as hyperalgesia and somatic signs and withdrawal-induced aversion in a dose-related manner. Our results indicate that the alpha 5 nAChR subunit plays a role in the effects of varenicline on nicotine reward in mice. Moreover, the mediation of alpha 5 nAChRs, but not beta 2 nAChRs are probably needed for aversive properties of varenicline at high dose. Varenicline was also shown to reduce several nicotine withdrawal signs. (C) 2018 Elsevier Ltd. All rights reserved.