Mechanism of action of the hypnotic zolpidem in vivo

Zolpidem is a widely used hypnotic agent acting at the GABA(A) receptor benzodiazepine site. On recombinant receptors, zolpidem displays a high affinity to α1-GABA(A) receptors, an intermediate affinity to α₂- and α₃-GABA(A) receptors and fails to bind to α₅GABA(A) receptors. However, it is not known which receptor subtype is essential for mediating the sedative-hypnotic action in vivo. Studying α1(H101R) mice, which possess zolpidem-insensitive α₁-GABA(A) receptors, we show that the sedative action of zolpidem is exclusively mediated by α₁-GABA(A) receptors. Similarly, the activity of zolpidem against pentylenetetrazole-induced tonic convulsions is also completely mediated by α₁-GABA(A) receptors. These results establish that the sedative-hypnotic and anticonvulsant activities of zolpidem are due to its action on α₁-GABA(A) receptors and not on α₂ or α₃GABA(A) receptors.