EPA Science Inventory

Effects of the Sazetidine-a Family of Compounds on the Body Temperature in Wildtype, Nicotinic Receptor B2(-/-) and a7(-/-) Mice

Citation:

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).

Description:

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.

Purpose/Objective:

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.

URLs/Downloads:

TAD-13-057-ABSTRACT.PDF   (PDF,NA pp, 270.925 KB,  about PDF)

Record Details:

Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Start Date: 10/15/2013
Completion Date: 10/15/2013
Record Last Revised: 08/08/2014
Record Created: 12/19/2013
Record Released: 12/19/2013
OMB Category: Other
Record ID: 265060

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB

TOXICOLOGY ASSESSMENT DIVISION

NEUROTOXICOLOGY BRANCH