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.

Fig. 1

Sazetidine-A dose-effect function (0.3-3 mg/kg) on core body temperature of mice over 4-hours post injection. The mean baseline temperature for the mice before drug dosing was 36.8±0.2°C. Data represent group mean values ± S.E.M. N=15/treatment.

Fig. 2

A) Effects of acute administration of nicotine (0.2, 0.4 and 0.8 mg/kg) on core body temperature in mice. Data represent means ± S.E.M. N=15. The mean baseline temperature for the mice before drug dosing was 37.1±0.1°C. B) Sazetidine-A (0.3 and 0.6 mg/kg) interactions with nicotine (0.4 mg/kg) and core body temperature in mice. Data represent means ± S.E.M. N=14. The mean baseline temperature for the mice before drug dosing was 37.0±0.1°C. C) Sazetidine-A (0.6 mg/kg) interactions with nicotine (0.8 mg/kg) and core body temperature in mice. Data represent means ± S.E.M. N=13. The mean baseline temperature for the mice before drug dosing was 36.7±0.2 °C.

Fig. 2

A) Effects of acute administration of nicotine (0.2, 0.4 and 0.8 mg/kg) on core body temperature in mice. Data represent means ± S.E.M. N=15. The mean baseline temperature for the mice before drug dosing was 37.1±0.1°C. B) Sazetidine-A (0.3 and 0.6 mg/kg) interactions with nicotine (0.4 mg/kg) and core body temperature in mice. Data represent means ± S.E.M. N=14. The mean baseline temperature for the mice before drug dosing was 37.0±0.1°C. C) Sazetidine-A (0.6 mg/kg) interactions with nicotine (0.8 mg/kg) and core body temperature in mice. Data represent means ± S.E.M. N=13. The mean baseline temperature for the mice before drug dosing was 36.7±0.2 °C.

Fig. 2

A) Effects of acute administration of nicotine (0.2, 0.4 and 0.8 mg/kg) on core body temperature in mice. Data represent means ± S.E.M. N=15. The mean baseline temperature for the mice before drug dosing was 37.1±0.1°C. B) Sazetidine-A (0.3 and 0.6 mg/kg) interactions with nicotine (0.4 mg/kg) and core body temperature in mice. Data represent means ± S.E.M. N=14. The mean baseline temperature for the mice before drug dosing was 37.0±0.1°C. C) Sazetidine-A (0.6 mg/kg) interactions with nicotine (0.8 mg/kg) and core body temperature in mice. Data represent means ± S.E.M. N=13. The mean baseline temperature for the mice before drug dosing was 36.7±0.2 °C.

Fig. 3

A) Effects of acute administration of DHβE (1, 3 and 6 mg/kg) on core body temperature in mice. Data represent means ± S.E.M. N=9. The mean baseline temperature for the mice before drug dosing was 37.2±0.2°C., B) Sazetidine-A (0.6 mg/kg) interactions with DHβE (3 mg/kg) and core body temperature in mice. Data represent means ± S.E.M. N=13. The mean baseline temperature for the mice before drug dosing was 37.2±0.1 °C.

Fig. 3

A) Effects of acute administration of DHβE (1, 3 and 6 mg/kg) on core body temperature in mice. Data represent means ± S.E.M. N=9. The mean baseline temperature for the mice before drug dosing was 37.2±0.2°C., B) Sazetidine-A (0.6 mg/kg) interactions with DHβE (3 mg/kg) and core body temperature in mice. Data represent means ± S.E.M. N=13. The mean baseline temperature for the mice before drug dosing was 37.2±0.1 °C.

Fig. 4

A). Dose-effect function of MLA on body temperature (mean±s.e.m.), B) Effects of acute administration of MLA (6 mg/kg) and sazetidine-A (0.6 mg/kg) on core body temperature in mice. Data represent means ± S.E.M. N=8. The mean baseline temperature for the mice before drug dosing was 37.0±0.1°C.

Fig. 4

A). Dose-effect function of MLA on body temperature (mean±s.e.m.), B) Effects of acute administration of MLA (6 mg/kg) and sazetidine-A (0.6 mg/kg) on core body temperature in mice. Data represent means ± S.E.M. N=8. The mean baseline temperature for the mice before drug dosing was 37.0±0.1°C.

Fig. 5

A) Effects of acute administration of sazetidine-A (1, 3 and 6 mg/kg) on core body temperature in rats. The mean baseline temperature for the rats before drug dosing was 38.1±0.1°C. B) Comparison of maximal sazetidine-A induced-hypothermia in rats and mice. C) Comparison of the time course of sazetidine-A induced-hypothermia in rats and mice over three hours. Data represent means ± S.E.M. N= 15 mice and 14 rats.

Fig. 5

A) Effects of acute administration of sazetidine-A (1, 3 and 6 mg/kg) on core body temperature in rats. The mean baseline temperature for the rats before drug dosing was 38.1±0.1°C. B) Comparison of maximal sazetidine-A induced-hypothermia in rats and mice. C) Comparison of the time course of sazetidine-A induced-hypothermia in rats and mice over three hours. Data represent means ± S.E.M. N= 15 mice and 14 rats.

Fig. 5

A) Effects of acute administration of sazetidine-A (1, 3 and 6 mg/kg) on core body temperature in rats. The mean baseline temperature for the rats before drug dosing was 38.1±0.1°C. B) Comparison of maximal sazetidine-A induced-hypothermia in rats and mice. C) Comparison of the time course of sazetidine-A induced-hypothermia in rats and mice over three hours. Data represent means ± S.E.M. N= 15 mice and 14 rats.