α4β2* Nicotinic Acetylcholine Receptors Modulate the Effects of Ethanol and Nicotine on the Acoustic Startle Response

Abstract

Background: Ethanol modulates the functional activity of α4β2 neuronal nicotinic cholinergic receptors (nAChR) when measured in vitro, but the potential role of α4β2 nAChRs in regulating behavioral effects of ethanol is unknown. Recently, Tritto et al. (Tritto T, Stitzel JA, Marks MJ, Romm E, Collins AC (2002) Variability in response to nicotine in the LS×SS RI strains: potential role of polymorphisms in alpha4 and alpha6 nicotinic receptor genes. Pharmacogenetics 12:197–208) reported that a polymorphism (A529T) in the α4 nAChR subunit gene is associated with variability in nicotine's effects on startle in the LS×SS recombinant inbred (RI) strains. Ethanol also alters the acoustic startle response. Thus, we evaluated the potential role of α4β2 nAChRs in modulating ethanol's effects on acoustic startle. Methods: The effects of ethanol on acoustic startle were determined in the LS×SS RI strains. In addition, the effects of ethanol and nicotine were also measured in α4 gain of function and β2 null mutant mice. The β2 mutants do not express the major variant of α4 nAChRs, α4β2. Results: An association between the α4 A529T polymorphism and ethanol's effects on startle was found in the LS×SS RI strains; those strains that express the A529 variant of α4 were more sensitive to ethanol‐induced depression of startle. The α4 gain of function mutants were more sensitive to the effects of both nicotine and ethanol and the β2 null mutants were less sensitive to both drugs. Conclusions: α4β2‐containing nAChRs may play important roles in modulating the effects of both ethanol and nicotine on the acoustic startle response. We suggest that nAChR subunit genes should be evaluated as potential contributors to both alcoholism and tobacco abuse.

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