Effects of sazetidine-A, a selective α4β2* nicotinic receptor desensitizing agent, on body temperature regulation in mice and rats

Abstract

Nicotine-induced hypothermia is well established, but the nicotinic receptor actions underlying this effect are not clear. Nicotine causes activation and desensitization at a variety of nicotinic receptor subtypes. Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol] is a novel compound that potently and selectively desensitizes α4β2* nicotinic receptors. The main goal of this study was to investigate the effects of sazetidine-A, on core body temperature (Tc) in mice and rats. Sazetidine-A effects on Tc and the interactions of sazetidine-A with nicotine and selective nicotinic antagonists were investigated to determine the receptor actions underlying nicotine-induced hypothermia. Adult male mice were injected with different dose of nicotine (0.2, 0.4 and 0.8 mg/kg), sazetidine-A (0.3, 1, and 3mg/kg), a mixture of nicotine (0.4 or 0.8 mg/kg) and sazetidine-A (0.3 or 0.6 mg/kg) or saline and Tc was monitored telemetrically. In another set of experiments, the interaction between sazetidine-A and dihydro-β-erythroidine (DHβE), an α4β2* nicotinic receptors antagonist, and methyllycaconitine (MLA), an α7 antagonist, was investigated. Tc of mice was monitored following DHβE (1, 3 and 6 mg/kg), a combination of DHβE (3mg/kg) and sazetidine-A (0.6 mg/kg), MLA (1.5, 3 or 6 mg/kg) or combination of MLA (6 mg/kg) and sazetidine (0.6 mg/kg) or saline. The acute effect of sazetidine-A (1, 3, and 6 mg/kg) on rats Tc was also studied. Acute sazetidine-A caused a pronounced and long-lasting hypothermia in mice; Tc decreased to about 28°C at 100 min and recovered within 230 min. The hypothermic effect of sazetidine in rats was much less in magnitude (about 3°C) and shorter in duration compared with that in mice. Nicotine co-administration with low doses of sazetidine potentiated the magnitude and duration of hypothermia in mice. The α4β2* nicotinic receptors antagonist DHβE significantly prolonged sazetidine-A-induced hypothermia but did not increase its depth. The α7 antagonist MLA caused a modest degree of hypothermia with relatively short duration in mice. MLA failed to counteract the sazetidine-A-induced hypothermia. Overall, our results show that pharmacological modulation of α4β2* nicotinic receptors elicits changes in body temperature that may involve desensitization of these receptors.