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The Journal of Neuroscience, July 16, 2003, 23(15):6255-6263

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Altered Anxiety-Related Responses in Mutant Mice Lacking the 4 Subunit of the Nicotinic Receptor

Ramiro Salas, Fredalina Pieri, Beryl Fung, John A. Dani, and Mariella De Biasi

Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030

Nicotine, acting at nicotinic acetylcholine receptors (nAChRs), is the primary addictive component of tobacco. Smokers often report an anxiolytic effect of cigarettes. This relief of anxiety, attributed to nicotine, is an important contributor to relapse when smokers try to quit. Hence, the study of the anxiolytic effects of nicotine is important for understanding the mechanisms underlying nicotine addiction. Mammalian nAChRs are pentameric ion channels usually composed of and subunits. Taking advantage of4-homozygous-null mice (4-/-), we examined the role of the nAChR 4 subunit in anxiety-related behaviors. The 4-/- mice behaved as though they were less anxious than wild-type littermates on the elevated-plus and staircase mazes, tests that measure anxiety-related behaviors. To obtain an independent, physiological indication of the stress produced by several tests, we measured changes in heart rate using telemetry. Consistently with the behavioral phenotype, 4-/- mice had a smaller heart rate increase in the elevated-plus maze than did wild-type littermates. In contrast, during social isolation, a separate test for anxiety,4-/- mice exhibited a greater increase in heart rate than did wild-type littermates. Finally, 4-/- mice were indistinguishable from their wild-type littermates in the open field, the light/dark box, and the mirrored chamber. The overall results demonstrate that 4-containing (4*) nAChRs influence behavioral responses during anxiety-related tests, and that this effect depends on the type of anxiety-provoking experience. Through their influence on anxiety-related behavior, 4* nAChRs might influence both tobacco consumption and smoking relapse.

Key words: nicotinic acetylcholine receptors; 4 subunit; anxiety; elevated-plus maze; open field; light/dark box; telemetry; heart rate

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Received Aug. 16, 2002; revised Apr. 23, 2003; accepted Apr. 30, 2003.

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