Contribution of the α1-GABA_A receptor subtype to the pharmacological actions of benzodiazepine site inverse agonists

A histidine-to-arginine point-mutation at position 101 in the α1-subunit of γ-aminobutyric acid (GABA)_A receptors has been shown to switch the in vitro efficacy of Ro 15-4513 from inverse agonism to agonism. In order to assess the consequences of this pharmacological switch in vivo, the motor and proconvulsant effects of Ro 15-4513 were analyzed in knock-in mice containing point-mutated α1(H101R)-GABA_A receptors. Furthermore the influence of the α1(H101R) substitution on the efficacy of the β-carboline inverse agonist DMCM was examined both in vitro and in vivo. Ro 15-4513 (10 mg/kg) increased baseline locomotion and potentiated the convulsant effect of pentylenetetrazole in wild type mice. In α1(H101R) mice, Ro 15-4513 decreased locomotion and, at a higher dose (30 mg/kg) it displayed an anticonvulsant action. In vitro, DMCM acted as an inverse agonist at recombinant α1β2γ2 receptors whereas it potentiated GABA-evoked chloride currents at α1(H101R)β2γ2 receptors. DMCM was inactive as a convulsant in α1(H101R) mice. In keeping with the major contribution of these receptors to the sedative and anticonvulsant properties of benzodiazepine site agonists, the present findings identify the α1-GABA_A receptors as the molecular targets for the allosteric modulation by benzodiazepine site ligands in either direction with regard to the behavioral outputs, sedation/motor stimulation and anticonvulsion/proconvulsion.