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.