Variability in the benzodiazepine response of serotonin 5-HT1A receptor null mice displaying anxiety-like phenotype: Evidence for genetic modifiers in the 5-HT-mediated regulation of GABAA receptors

Abstract

Benzodiazepines (BZs) acting as modulators of GABAA receptors (GABAARs) 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 GABAARs. 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-Hydroxytryptamine1A receptor (5-HT1AR) 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 GABAAR subunits α1 and α2. Here, we show that R -/- mice on the C57B16 (B6) background also have anxiety phenotype, but they respond to BZ and have normal GABAAR subunit expression. This indicates that the 5-HT1AR-mediated regulation of GABA AR α 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-HT1AR on the expression of GABAAR a subunits. In addition, we show that this genetic interaction in SW mice operates early in postnatal life to influence the expression of GABAAR α subunits at the transcriptional level. These data indicate that BZ-resistant anxiety results from a developmental arrest of GABAAR expression in SW-R -/- mice, and a similar mechanism may be responsible for the BZ insensitivity of some anxiety patients.