ACCELERATED COMMUNICATION Molecular Targets for the Myorelaxant Action of Diazepam

Diazepam is used clinically for its myorelaxant, anxiolytic, sed-ative, and anticonvulsant properties. Although the anxiolytic action is mediated by a2 g-aminobutyric acid A (GABAA) re-ceptors, the sedative action and in part the anticonvulsant action are mediated by a1 GABAA receptors. To identify the GABAA receptor subtypes mediating the action of diazepam on muscle tone, we have assessed the myorelaxant properties of diazepam in a2(H101R) and a3(H126R) knock-in mice harbor-ing diazepam-insensitive a2 or a3 GABAA receptors, respec-tively. Whereas in a2(H101R) mice the myorelaxant action of diazepam was almost completely abolished at doses up to 10 mg/kg, the same dose induced myorelaxation in both wild-type and a3(H126R) mice. It was only at a very high dose (30 mg/kg diazepam) that a2(H101R) mice showed partial myorelaxation and a3(H126R) mice were partially protected from myorelax-ation compared with wild-type mice. Thus, the myorelaxant activity of diazepam seems to be mediated primarily by a2 GABAA receptors and at high concentrations also by a3 GABAA receptors. Classical benzodiazepines are in wide clinical use as hyp-notics, tranquilizers, muscle relaxants, and anticonvulsants. These effects are caused exclusively by their interaction with the benzodiazepine site of GABAA receptors. Based on the presence of more than a dozen subunit genes, the central nervous system contains a plethora of structurally divers