title: Effects of the sazetidine-a family of compounds on the body temperature in wildtype, nicotinic receptor β2-/- and α7-/- mice.
abstract: Nicotine elicits hypothermic responses in rodents. This effect appears to be related to nicotinic receptor desensitization because sazetidine-A, an α4β2 nicotinic receptor desensitizing agent, produces marked hypothermia and potentiates nicotine-induced hypothermia in mice. To determine the specificity of sazetidine-A induced hypothermia to β2 subunit-containing nicotinic receptors, we tested its efficacy in β2 knockout (β2(-/-)) mice. These effects were compared with wildtype (WT) and α7 knockout (α7(-/-)) 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 β2(-/-) mice. This indicates that the greater proportion of sazetidine-A induced hypothermia is mediated via actions on β2-containing nicotinic receptors, while a smaller component of hypothermia induced by sazetidine-A is mediated by non-β2 receptors. Similar to WT mice, α7(-/-) mice showed the full extent of the sazetidine-A effect, suggesting that the hypothermia produced by sazetidine-A did not depend on actions on α7 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 α7(-/-) mice. Furthermore, unlike sazetidine-A, triazetidine-O and YL-1-127 did not show any hint of a hypothermic effect in β2(-/-) mice. VMY-2-95 like sazetidine-A did show a residual hypothermic effect in the β2(-/-) 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 β2 subunit, but that a small component of the effect is apparently mediated by non-β2 containing receptors.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, USA. Electronic address: edlevin@duke.edu.
authors.forename: Edward D
authors.initials: ED
authors.lastname: Levin
authors.forename: Hannah G
authors.initials: HG
authors.lastname: Sexton
authors.forename: Karen
authors.initials: K
authors.lastname: Gordon
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Gordon
authors.forename: Yingxian
authors.initials: Y
authors.lastname: Xiao
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Kellar
authors.forename: Venkata Mahidhar
authors.initials: VM
authors.lastname: Yenugonda
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Michael P
authors.initials: MP
authors.lastname: White
authors.forename: Mikell
authors.initials: M
authors.lastname: Paige
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
authors.forename: Amir H
authors.initials: AH
authors.lastname: Rezvani
mesh_terms: D000818:Animals; D001384:Azetidines / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects*; D055786:Gene Knockout Techniques; D008297:Male; D051379:Mice; D011725:Pyridines / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D001384:Azetidines; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C514816:sazetidine-A
keywords: Desensitization; Knockout; Nicotinic; Sazetidine-A; Temperature regulation
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