HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 31/3/422    most recent 00063.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Tapper, A. R. Articles by Lester, H. A. Search for Related Content PubMed PubMed Citation Articles by Tapper, A. R. Articles by Lester, H. A.

Nicotine responses in hypersensitive and knockout 4 mice account for tolerance to both hypothermia and locomotor suppression in wild-type mice

¹ Division of Biology, California Institute of Technology, Pasadena, California
² Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado
³ Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts

Nicotinic receptors containing the 4 subunit (4* nAChRs) have high sensitivity and are widely expressed in the central nervous system, yet their contributions to behavioral tolerance, a hallmark of nicotine dependence, are unclear. To evaluate the contribution of 4* and non-4 nAChRs in the development of tolerance to hypothermia and locomotor suppression, 4 knockout (KO), hypersensitive Leu9'Ala 4 knock-in, and wild-type (WT) mice received daily nicotine injections, and their behaviors were compared. Repeated selective activation of 4* nAChRs in Leu9'Ala mice produced profound tolerance to hypothermia over 7 days, whereas no tolerance was observed in 4 KO animals. The summed time course and temperature response (after appropriate normalizations) from these two mutant mouse strains resembled the time course of WT tolerance. In addition, daily selective activation of 4* nAChRs elicited locomotor activation in Leu9'Ala mice, but nicotine suppressed activity in 4 KO mice and this did not change with daily drug exposure. Again, appropriately combined responses from the two mutant strains resembled the biphasic nicotine-induced activity in WT animals. Thus, by analyzing nicotinic responses in two complementary mouse lines, one lacking 4* nAChRs, the other expressing hypersensitive 4* nAChRs, one can accurately separate non-4 nAChR responses from 4 nAChR responses, and one can also account for WT tolerance to both hypothermia and locomotor suppression. Our study suggests a new paradigm for bridging the gap between genetic manipulation of a single receptor and whole animal behavioral studies and shows that activation of 4* nAChRs is both necessary and sufficient for the expression of tolerance.

addiction; nicotinic receptors; locomotion

This article has been cited by other articles:

				X. A. Perez, T. Bordia, J. M. McIntosh, S. R. Grady, and M. Quik Long-Term Nicotine Treatment Differentially Regulates Striatal {alpha}6{alpha}4{beta}2* and {alpha}6(Non{alpha}4){beta}2* nAChR Expression and Function Mol. Pharmacol., September 1, 2008; 74(3): 844 - 853. [Abstract] [Full Text] [PDF]

				X. M. Shao, W. Tan, J. Xiu, N. Puskar, C. Fonck, H. A. Lester, and J. L. Feldman {alpha}4* Nicotinic Receptors in preBotzinger Complex Mediate Cholinergic/Nicotinic Modulation of Respiratory Rhythm J. Neurosci., January 9, 2008; 28(2): 519 - 528. [Abstract] [Full Text] [PDF]