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Effects of the Sazetidine-a Family of Compounds on the Body Temperature in Wildtype, Nicotinic Receptor B2(-/-) and a7(-/-) Mice
Levin, E., H. Sexton, K. Gordon, C. Gordon, Y. Xiao, K. Kellar, V. Mahidhar Yenugonda, Y. Liu, M. White, M. Paige, M. Brown, AND A. Rezvani. Effects of the Sazetidine-a Family of Compounds on the Body Temperature in Wildtype, Nicotinic Receptor B2(-/-) and a7(-/-) Mice. European Journal of Pharmacology. Elsevier Science Ltd, New York, NY, 718(1):167-72, (2013).
Nicotine elicits hypothermic responses in rodents. This effect appears to be related to nicotinic receptor desensitization because sazetidine-A, an a4B2 nicotinic receptor desensitizing agent, produces marked hypothermia and potentiates nicotine-induced hypothermia in mice. To determine the specificity of sazetidine-A induced hypothermia to B2 subunit-containing nicotinic receptors, we tested its efficacy in B2 knockout (B2-/-) mice. These effects were compared with wildtype (WT) and a7 knockout (a7-/-) mice. Confirming our earlier results, sa.zetidine-A elicited a pronounced and long-lasting hypothermia in WT mice. In comparison, sazetidine-A induced a much attenuated and shorter hypothermic response in B2-/- mice. This indicates that the greater proportion of sazetidine-A induced hypothermia is mediated via actions on B2-containing nicotinic receptors, while a smaller component of hypothermia induced by sazetidine-A is mediated by non-B2 nicotinic receptors. Similar to WT mice, a7-/- mice showed the full extent of the sazetidine-A effect, suggesting that the hypothermia produced by sazetidine-A did not depend on actions on a7 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 a7-/- mice. Furthermore, unlike sazetidine-A, triazetidine-O and YL1-127 did not show any hint of a hypothermic effect in B2-/- mice. VMY-2-95 like sazetidine-A did show a residual hypothermic effect in the B2-/- 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 B2 subunit, but that a small component of the effect is apparently mediated by non-B2 containing receptors.
This is a paper from Duke University in which Dr. Christopher Gordon contributed assistance with the analysis and interpretation of the data and was added as a co-author.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
TOXICOLOGY ASSESSMENT DIVISION