It is the long-term objective of this proposal to identify inbred mouse strains that express functionally distinct isoforms of the neuronal nicotinic receptor subunits alpha3, alpha4, alpha6, alpha7, and beta2. These subunits were chosen based on their potential roles in mediating the dependence-causing actions of nicotine. Identification of functionally distinct nicotinic receptor isoforms will be initiated by mutation analysis of the exons of the genes that encode these receptor subunits. Approximately forty inbred mouse strains of distinct genetic origins will be evaluated in the mutation screen. Once the mutation screen identifies nicotinic receptor subunit isoforms in mice with amnino acid differences, the appropriate cDNAs will be generated. Subsequently, the variant nicotinic receptor subunit isoforms will be evaluated in vitro for their pharmacological and functional properties. These experiments will lead to the establishment of a catalogue of mouse strains with known variations in nicotinic receptor subtype functional properties. This catalogue of mouse strains will serve as an important additional resource to evaluate the role of the various nicotinic receptor subunits in modulating the dependence-causing actions of nicotine. It has been estimated that 25 percent of all premature deaths in the United States are due to tobacco use. Despite the widespread knowledge of the health risks of smoking, approximately 25 percent of adults in the United States continue to smoke. Among smokers, nearly 80 percent say that they would like to quit although less than 5 percent successfully do so. It is well established that nicotine is the major dependence-causing agent in tobacco and that the initial actions of nicotine in the brain are mediated by nicotinic acetyicholine receptors. However, which nicotinic receptor subtypes mediate the dependence-causing actions of nicotine is poorly understood. To date, only modest success, at best, has been achieved in resolving this issue. The mouse strain nicotinic receptor """"""""function"""""""" catalogue that will result from the studies outlined in this proposal will add a valuable resource for addressing this issue. By elucidating which nicotinic receptor subtypes are critical for the establishment of nicotine dependence, more effective pharmacological strategies for smoking cessation may be developed.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA014369-02
Application #
6515920
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (01))
Program Officer
Satterlee, John S
Project Start
2001-08-01
Project End
2005-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
2
Fiscal Year
2002
Total Cost
$219,625
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pharmacology
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Wilking, Jennifer A; Stitzel, Jerry A (2015) Natural genetic variability of the neuronal nicotinic acetylcholine receptor subunit genes in mice: Consequences and confounds. Neuropharmacology 96:205-12
Wilking, Jennifer A; Hesterberg, Kirstin G; Crouch, Eric L et al. (2010) Chrna4 A529 knock-in mice exhibit altered nicotine sensitivity. Pharmacogenet Genomics 20:121-30
Papke, Roger L; Wecker, Lynn; Stitzel, Jerry A (2010) Activation and inhibition of mouse muscle and neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes. J Pharmacol Exp Ther 333:501-18
Saccone, Nancy L; Saccone, Scott F; Hinrichs, Anthony L et al. (2009) Multiple distinct risk loci for nicotine dependence identified by dense coverage of the complete family of nicotinic receptor subunit (CHRN) genes. Am J Med Genet B Neuropsychiatr Genet 150B:453-66
Brooks, Nathanial P; Mexal, Sharon; Stitzel, Jerry A (2009) Chrna7 genotype is linked with alpha7 nicotinic receptor expression but not alpha7 RNA levels. Brain Res 1263:1-9
Hutchison, Kent E; Haughey, Heather; Niculescu, Michelle et al. (2008) The incentive salience of alcohol: translating the effects of genetic variant in CNR1. Arch Gen Psychiatry 65:841-50
Stitzel, Jerry A (2008) Naturally occurring genetic variability in the nicotinic acetylcholine receptor alpha4 and alpha7 subunit genes and phenotypic diversity in humans and mice. Front Biosci 13:477-91
Bierut, Laura Jean; Stitzel, Jerry A; Wang, Jen C et al. (2008) Variants in nicotinic receptors and risk for nicotine dependence. Am J Psychiatry 165:1163-71
Mexal, Sharon; Jenkins, Paul M; Lautner, Meeghan A et al. (2007) alpha7 nicotinic receptor gene promoter polymorphisms in inbred mice affect expression in a cell type-specific fashion. J Biol Chem 282:13220-7
Chadman, Kathryn K; Woods, James H; Stitzel, Jerry (2007) Chlorisondamine inhibits the nicotine-induced stimulation of c-fos in the pigeon brain for up to 2 weeks. Nicotine Tob Res 9:927-36

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