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Nicotine responses in hypersensitive and knockout α4 mice account for tolerance to both hypothermia and locomotor suppression in wild-type mice

Tapper, Andrew R. and McKinney, Sheri L. and Marks, Michael J. and Lester, Henry A. (2007) Nicotine responses in hypersensitive and knockout α4 mice account for tolerance to both hypothermia and locomotor suppression in wild-type mice. Physiological Genomics, 31 (3). pp. 422-428. ISSN 1094-8341. doi:10.1152/physiolgenomics.00063.2007. https://resolver.caltech.edu/CaltechAUTHORS:20200424-071823168

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Abstract

Nicotinic receptors containing the α4 subunit (α4* 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 α4* and non-α4 nAChRs in the development of tolerance to hypothermia and locomotor suppression, α4 knockout (KO), hypersensitive Leu9′Ala α4 knock-in, and wild-type (WT) mice received daily nicotine injections, and their behaviors were compared. Repeated selective activation of α4* nAChRs in Leu9′Ala mice produced profound tolerance to hypothermia over 7 days, whereas no tolerance was observed in α4 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 α4* nAChRs elicited locomotor activation in Leu9′Ala mice, but nicotine suppressed activity in α4 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 α4* nAChRs, the other expressing hypersensitive α4* nAChRs, one can accurately separate non-α4 nAChR responses from α4 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 α4* nAChRs is both necessary and sufficient for the expression of tolerance.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1152/physiolgenomics.00063.2007DOIArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2007 the American Physiological Society. Received 17 March 2007; Accepted 19 August 2007; Published online 1 November 2007; Published in print 1 November 2007. Funding from National Research Service Award (A. R. Tapper), National Institute of Drug Abuse Grants DA-17279 and DA-19375, California Tobacco-Related Disease Research Program, and Philip Morris USA/International is gratefully acknowledged.
Funders:
Funding AgencyGrant Number
NIH Predoctoral FellowshipUNSPECIFIED
NIHDA-17279
NIHDA-19375
California Tobacco-Related Disease Research ProgramUNSPECIFIED
Philip Morris USA/InternationalUNSPECIFIED
Subject Keywords:addiction; nicotinic receptors; locomotion
Issue or Number:3
DOI:10.1152/physiolgenomics.00063.2007
Record Number:CaltechAUTHORS:20200424-071823168
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200424-071823168
Official Citation:Nicotine responses in hypersensitive and knockout α4 mice account for tolerance to both hypothermia and locomotor suppression in wild-type mice. Andrew R. Tapper, Sheri L. McKinney, Michael J. Marks, and Henry A. Lester. Physiological Genomics 2007 31:3, 422-428; doi: 10.1152/physiolgenomics.00063.2007
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102763
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:24 Apr 2020 14:35
Last Modified:16 Nov 2021 18:15

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