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The Journal of Neuroscience, July 14, 2004, 24(28):6343-6351; doi:10.1523/JNEUROSCI.0563-04.2004

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Cellular/Molecular
Variability in the Benzodiazepine Response of Serotonin 5-HT_1A Receptor Null Mice Displaying Anxiety-Like Phenotype: Evidence for Genetic Modifiers in the 5-HT-Mediated Regulation of GABA_A Receptors

Sarah J. Bailey and Miklos Toth

Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10021

Benzodiazepines (BZs) acting as modulators of GABA_A receptors (GABA_ARs) are an important group of drugs for the treatment of anxiety disorders. However, a large inter-individual variation in BZ sensitivity occurs in the human population with some anxiety disorder patients exhibiting diminished sensitivity to BZ and reduced density of GABA_ARs. The mechanism underlying BZ treatment resistance is not known, and it is not possible to predict whether an anxiety patient will respond to BZ. 5-Hydroxytryptamine_1A receptor (5-HT_1AR) null mice (R^-/-) on the Swiss-Webster (SW) background reproduce several features of BZ-resistant anxiety; they exhibit anxiety-related behaviors, do not respond to BZ, have reduced BZ binding, and have decreased expression of the major GABA_AR subunits 1 and 2. Here, we show that R^-/- mice on the C57Bl6 (B6) background also have anxiety phenotype, but they respond to BZ and have normal GABA_AR subunit expression. This indicates that the 5-HT_1AR-mediated regulation of GABA_AR subunit expression is subject to genetic modification. Hybrid SW/B6-R^-/- mice also exhibit BZ-resistant anxiety, suggesting that SW mice carry a genetic modifier, which mediates the effect of the 5-HT_1AR on the expression of GABA_AR subunits. In addition, we show that this genetic interaction in SW mice operates early in postnatal life to influence the expression of GABA_AR subunits at the transcriptional level. These data indicate that BZ-resistant anxiety results from a developmental arrest of GABA_AR expression in SW-R^-/- mice, and a similar mechanism may be responsible for the BZ insensitivity of some anxiety patients.

Key words: anxiety; benzodiazepine; GABA; serotonin; mouse; neurotransmitter

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Received Nov 26, 2003; revised May 28, 2004; accepted May 31, 2004.

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