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 α 2 ‐ and α 3 ‐GABA A receptors and fails to bind to α 5 ‐GABA 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 α 1 ‐GABA A receptors, we show that the sedative action of zolpidem is exclusively mediated by α 1 ‐GABA A receptors. Similarly, the activity of zolpidem against pentylenetetrazole‐induced tonic convulsions is also completely mediated by α 1 ‐GABA A receptors. These results establish that the sedative‐hypnotic and anticonvulsant activities of zolpidem are due to its action on α 1 ‐GABA A receptors and not on α 2 ‐ or α 3 ‐GABA A receptors. British Journal of Pharmacology (2000) 131 , 1251–1254; doi: 10.1038/sj.bjp.0703717