Nelotanserin, a selective 5-HT2A receptor inverse agonist, attenuates aspects of nicotine withdrawal but not reward in mice

Abstract

Nicotine smoking contributes to many preventable disabilities, diseases and deaths. Targeting nicotine reward and withdrawal is a basis for the majority of smoking cessation pharmacotherapies. Due to the emergence of interest in 5-HT2A receptor modulators for numerous psychiatric disorders, we investigated the effect of nelotanserin, a 5-HT2A receptor inverse agonist, on nicotine reward and withdrawal in ICR mice. In nicotine-dependent mice, nelotanserin dose-dependently reduced somatic signs of nicotine withdrawal and thermal hyperalgesia as measured in the hot plate test. However, nelotanserin had no effect on anxiety-like behavior and failed to reduce nicotine reward as measured in the conditioned place preference test. Our results suggest that inverse agonism of the 5-HT2A receptor may be a feasible novel mechanism for smoking cessation by reducing both physical withdrawal and thermal hyperalgesia associated with nicotine abstinence but may require complementary pharmacotherapies targeting affective and reward-associated decrements to improve cessation outcomes.