ORIGINAL ARTICLESChrna4 A529 knock-in mice exhibit altered nicotine sensitivityWilking, Jennifer A.a b; Hesterberg, Kirstin G.a; Crouch, Eric L.a; Homanics, Gregg E.c; Stitzel, Jerry A.a bAuthor Information aInstitute for Behavioral Genetics bDepartment of Integrative Physiology, University of Colorado, Boulder, Colorado cDepartment of Anesthesiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Correspondence to Dr Jerry A. Stitzel, PhD, Institute for Behavioral Genetics, University of Colorado UCB 447, Boulder, Colorado 80309, USA Tel: +1 303 735 6173; fax: +1 303 492 8063; e-mail: [email protected] Present address: Jennifer A. Wilking, Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada Received 26 October 2009 Accepted 14 December 2009 Pharmacogenetics and Genomics: February 2010 - Volume 20 - Issue 2 - p 121-130 doi: 10.1097/FPC.0b013e3283369347 Buy Metrics Abstract The reasons why people smoke are varied, but research has shown that genetic influences on various aspects of nicotine addiction are a major factor. There also is a strong genetic influence on measures of nicotine sensitivity in mice. Despite the established contribution of genetics to nicotine sensitivity in mice and humans, no naturally occurring genetic variation has been identified that demonstrably alters sensitivity to nicotine in either species. However, one genetic variant has been implicated in altering nicotine sensitivity in mice is a T529A polymorphism in Chrna4, the gene that encodes the nicotinic receptor (nAChR) α4 subunit. The Chrna4 T529A polymorphism leads to a threonine to alanine substitution at position 529 of the α4 subunit. To more definitively address whether the Chrna4 T529A polymorphism does, in fact, influence sensitivity to nicotine, knock-in mice were generated in which the threonine codon at position 529 was mutated to an alanine codon. Compared with Chrna4 T529 littermate controls, the Chrna4 A529 knock-in mice exhibited greater sensitivity to the hypothermic effects of nicotine, reduced oral nicotine consumption and did not develop conditioned place preference to nicotine. The Chrna4 A529 knock-in mice also differed from T529 littermates for two parameters of acetylcholine-stimulated 86Rb+ efflux in midbrain: maximal efflux and the percentage of α4β2* receptors with high sensitivity to activation by agonists. Results indicate that the polymorphism affects the function of midbrain α4β2* nAChRs and contributes to individual differences in several behavioral and physiological responses to nicotine thought to be modulated by midbrain α4β2* nAChRs. © 2010 Lippincott Williams & Wilkins, Inc.