Received for publication May 3, 2006.
Revised September 11, 2006.
Accepted for publication September 11, 2006.

The Anxioselective Agent DOV 51892 is More Efficacious than Diazepam at Enhancing GABA-Gated Currents at ₁ Subunit Containing GABA_A Receptors

Abstract

Studies using mice with point mutations of GABA_A receptor subunits suggest that the sedative and anxiolytic properties of 1,4-benzodiazepines are mediated, respectively, by GABA_A receptors bearing the ₁ and ₂ subunits. This hypothesis predicts that a compound with high efficacy at GABA_A receptors containing the ₁ subunit would produce sedation while an agonist acting at ₂ subunit containing receptors (with low or null efficacy at ₁ containing receptors) would be anxioselective. Electrophysiological studies using recombinant GABA_A receptors expressed in Xenopus oocytes indicate that maximal potentiation of GABA-stimulated currents by the pyrazolo-[1,5 a]-pyrimidine DOV 51892 at _122S constructs of the GABA_A receptor was significantly higher (148%) than diazepam. In contrast, DOV 51892 was considerably less efficacious and/or potent than diazepam in enhancing GABA-stimulated currents mediated by constructs containing ₂, ₃, or ₅ subunits. In vivo, DOV 51892 increased punished responding in the Vogel conflict test; an effect blocked by flumazenil, and increased the percent time spent in the open arms of the elevated plus maze. However, DOV 51892 had no consistent effects on motor function or muscle relaxation at doses more than one order of magnitude greater than the minimum effective anxiolytic dose. While the mutant mouse data predicts that the high-efficacy potentiation of GABA_A1a receptor-mediated currents by DOV 51892 would be sedating, behavioral studies demonstrate that DOV 51892 is anxioselective, indicating that GABA potentiation mediated by ₁ subunit containing GABA_A receptors may be neither the sole mechanism nor highly predictive of the sedative properties of benzodiazepine recognition site modulators.

Key words: Anxiety, Behavior, Benzodiazepine, Electrophysiology, GABAA Receptors, Sedation

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