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A Polymorphism in the α4 Nicotinic Receptor Gene (Chrna4) Modulates Enhancement of Nicotinic Receptor Function by Ethanol
Author(s) -
Butt Christopher M.,
Hutton Scott R.,
Stitzel Jerry A.,
Balogh Seth A.,
Owens Jeremy C.,
Collins Allan C.
Publication year - 2003
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1097/01.alc.0000067973.41153.bc
Subject(s) - nicotine , nicotinic acetylcholine receptor , nicotinic agonist , chemistry , ethanol , microbiology and biotechnology , acetylcholine receptor , biology , biochemistry , receptor , genetics , neuroscience
Background: Several studies indicate that ethanol enhances the activity of α4β2 nicotinic acetylcholine receptors (nAChR). Our laboratory has identified a polymorphism in the α4 gene that results in the substitution of an alanine (A) for threonine (T) at amino acid position 529 in the second intracellular loop of the α4 protein. Mouse strains expressing the A variant have, in general, greater nAChR‐mediated 86 Rb + efflux in response to nicotine than strains with the T variant. However, the possibility of the polymorphism modulating the effects of ethanol on the 86 Rb + efflux response has not been investigated. Methods: We have used the 86 Rb + efflux method to study the acute effects of ethanol on the function of the α4β2 nAChR in the thalamus in six different mouse strains. Experiments were also performed on tissue samples taken from F2 intercross animals. The F2 animals were derived from A/J mice crossed with a substrain of C57BL/6J mice that carried a null mutation for the gene encoding the β2 nAChR subunit. Results: In strains carrying the A polymorphism (A/J, AKR/J, C3H/Ibg), coapplication of ethanol (10–100 mM) with nicotine (0.03–300 μM) increased maximal ion flux when compared with nicotine alone with no effect on agonist potency. In contrast, ethanol had little effect on the nicotine concentration‐response curve in tissue prepared from strains carrying the T polymorphism (Balb/Ibg, C57BL/6J, C58/J). Experiments with the F2 hybrids demonstrated that one copy of the A polymorphism was sufficient to produce a significant enhancement of nAChR function by ethanol (50 mM) in animals that were also β2 +/+. Ethanol had no effect on nicotine concentration‐response curves in T/T β2 +/+ animals. Conclusions: The results suggest that the A/T polymorphism influences the initial sensitivity of the α4β2 nAChR to ethanol.