Molecular targets for the myorelaxant action of diazepam

Diazepam is used clinically for its myorelaxant, anxiolytic, sedative, and anticonvulsant properties. Although the anxiolytic action is mediated by al pha2 gamma -aminobutyric acid A (GABA(A)) receptors, the sedative action an d in part the anticonvulsant action are mediated by alpha1 GABA(A) receptor s. To identify the GABA(A) receptor subtypes mediating the action of diazep am on muscle tone, we have assessed the myorelaxant properties of diazepam in alpha2(H101R) and alpha3(H126R) knock-in mice harboring diazepam-insensi tive alpha2 or alpha3 GABA(A) receptors, respectively. Whereas in alpha2( H 101R) mice the myorelaxant action of diazepam was almost completely abolish ed at doses up to 10 mg/kg, the same dose induced myorelaxation in both wil d-type and alpha3( H126R) mice. It was only at a very high dose (30 mg/kg d iazepam) that alpha2( H101R) mice showed partial myorelaxation and alpha3( H126R) mice were partially protected from myorelaxation compared with wild- type mice. Thus, the myorelaxant activity of diazepam seems to be mediated primarily by alpha2 GABA(A) receptors and at high concentrations also by al pha3 GABAA receptors.