RT Journal Article
SR Electronic
T1 Molecular Targets for the Myorelaxant Action of Diazepam
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 442
OP 445
DO 10.1124/mol.59.3.442
VO 59
IS 3
A1 Florence Crestani
A1 Karin Löw
A1 Ruth Keist
A1 Marie-Juliette Mandelli
A1 Hanns Möhler
A1 Uwe Rudolph
YR 2001
UL http://molpharm.aspetjournals.org/content/59/3/442.abstract
AB Diazepam is used clinically for its myorelaxant, anxiolytic, sedative, and anticonvulsant properties. Although the anxiolytic action is mediated by α2 γ-aminobutyric acid A (GABAA) receptors, the sedative action and in part the anticonvulsant action are mediated by α1 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 α2(H101R) and α3(H126R) knock-in mice harboring diazepam-insensitive α2 or α3 GABAA receptors, respectively. Whereas in α2(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 α3(H126R) mice. It was only at a very high dose (30 mg/kg diazepam) that α2(H101R) mice showed partial myorelaxation and α3(H126R) mice were partially protected from myorelaxation compared with wild-type mice. Thus, the myorelaxant activity of diazepam seems to be mediated primarily by α2 GABAA receptors and at high concentrations also by α3 GABAA receptors.