Inverse agonists of the 5-HT2A receptor reduce nicotine withdrawal signs in rats

Abstract

Previous work has shown that chronic nicotine administration causes adaptive changes in 5-HT2A receptor expression. Based on this relationship, it was hypothesized that inactivating 5-HT2A receptors with the inverse agonists pimavanserin and volinanserin (MDL100907), would reduce the symptoms of nicotine withdrawal syndrome. Sprague-Dawley rats were rendered nicotine-dependent by subcutaneous infusion of nicotine bitartrate, 9\u2009mg/kg/day for seven days. The infusions were then terminated, and 22\u2009hours later, rats were observed under blind conditions for somatically expressed behavioral nicotine withdrawal signs. One hour before observations, the nicotine dependent rats were injected i.p. with saline alone, or either 0.3 or 1.0\u2009mg/kg pimavanserin in saline. Total withdrawal signs were reduced in a dose-dependent manner. A one-way ANOVA (total withdrawal signs as a function of dose) was highly significant, as was the descending linear trend of withdrawal signs as a function of dose. The 1.0\u2009mg/kg dose reduced withdrawal signs nearly to the level exhibited by a comparison group of non-dependent rats injected with saline. A second experiment was conducted in a similar manner, which showed that that volinanserin at 1.0\u2009mg/kg but not 0.25\u2009mg/kg also reduced nicotine withdrawal signs to nearly the level of non-dependent rats. In vitro experiments demonstrated that both pimavanserin and volinanserin potently antagonize 5-HT2A receptors, with approximately 25-fold, and 300-fold selectivity over 5-HT2C receptors, respectively. The results suggest that the 5-HT2A receptor contributes to mediating nicotine withdrawal syndrome, and thus represents a potential target for interventions to aid smoking cessation.