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BEHAVIORAL PHARMACOLOGY

Interaction of the Nicotinic Cholinergic System with Ethanol Withdrawal

Institute for Behavioral Genetics, University of Colorado, Boulder, Boulder, Colorado

The observation that alcohol and nicotine are commonly abused together suggests that the two drugs have common sites of action. In vitro studies indicate that nicotinic acetylcholine receptor (nAChR) function is enhanced by ethanol. Furthermore, some ethanol-related behaviors are associated with a region of mouse chromosome 2 that contains the gene encoding the 4 subunit of the nAChR (Chrna4). We have identified a polymorphism in Chrna4 that results in an alanine (A) or threonine (T) residue at position 529 in the second intracellular loop of the protein. Nicotinic receptors expressing the A variant have greater responses to nicotine and ethanol than receptors with the T variant when measured in vitro, but the possible effects of the polymorphism on the severity of ethanol withdrawal have not been assessed. The handling-induced convulsion (HIC) assay is an established method for studying drug withdrawal in vivo. We monitored the HIC responses of mice for 8 h after an injection of ethanol (4 g/kg). A survey of 16 mouse strains, as well as previously published data, indicated an association of the A/T polymorphism with ethanol withdrawal. This association was also found in wild-type animals from an F2 intercross of the A/J (A529-genotype) strain with C57BL/6J (T529-genotype) mice that also lack expression of the 2 nAChR subunit. 2 –/– animals, which do not express 42 nAChRs in the brain, exhibited significantly lower HIC responses and no effect of the polymorphism. These results suggest that the nicotinic cholinergic system and the A/T polymorphism modulate ethanol withdrawal.

Address correspondence to: Dr. Allan C. Collins, Institute for Behavioral Genetics, University of Colorado, Campus Box 447, Boulder, CO 80309-0447. E-mail: al.collins{at}colorado.edu

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