Levin_2013_Eur.J.Pharmacol_718_167

Nicotine elicits hypothermic responses in rodents. This effect appears to be related to nicotinic receptor desensitization because sazetidine-A, an alpha4beta2 nicotinic receptor desensitizing agent, produces marked hypothermia and potentiates nicotine-induced hypothermia in mice. To determine the specificity of sazetidine-A induced hypothermia to beta2 subunit-containing nicotinic receptors, we tested its efficacy in beta2 knockout (beta2(-/-)) mice. These effects were compared with wildtype (WT) and alpha7 knockout (alpha7(-/-)) mice. Confirming our earlier results, sazetidine-A elicited a pronounced and long-lasting hypothermia in WT mice. In comparison, sazetidine-A induced a much attenuated and shorter hypothermic response in beta2(-/-) mice. This indicates that the greater proportion of sazetidine-A induced hypothermia is mediated via actions on beta2-containing nicotinic receptors, while a smaller component of hypothermia induced by sazetidine-A is mediated by non-beta2 receptors. Similar to WT mice, alpha7(-/-) mice showed the full extent of the sazetidine-A effect, suggesting that the hypothermia produced by sazetidine-A did not depend on actions on alpha7 nicotinic receptor subtype. Three other novel nicotinic receptor desensitizing agents derived from sazetidine-A, triazetidine-O, VMY-2-95 and YL-1-127 also produced hypothermia in WT and alpha7(-/-) mice. Furthermore, unlike sazetidine-A, triazetidine-O and YL-1-127 did not show any hint of a hypothermic effect in beta2(-/-) mice. VMY-2-95 like sazetidine-A did show a residual hypothermic effect in the beta2(-/-) mice. These studies show that the hypothermic effects of sazetidine-A and the related compound VMY-2-95 are mainly mediated by nicotinic receptors containing beta2 subunit, but that a small component of the effect is apparently mediated by non-beta2 containing receptors.