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 alpha 1-GABA(A) receptors, an intermediate affinity to alpha(2)- and alpha(3)-GABA(A) receptors and fails to bind to alpha(5)-GABA(A) receptors. However, it is not known which receptor subtype is essential for mediating the sedative-hypnotic action in vivo. Studying alpha1(H101R) mice, which possess zolpidem-insensitive alpha(1)-GABA(A) receptors, we show that the sedative action of zolpidem is exclusively mediated by alpha(1)-GABA(A) receptors. Similarly, the activity of zolpidem against pentylenetetrazole-induced tonic convulsions is also completely mediated by alpha(1)-GABA(A) receptors. These results establish that the sedative-hypnotic and anticonvulsant activities of zolpidem are due to its action on alpha(1)-GABA(A) receptors and not on alpha(2)- or alpha(3)-GABA(A) receptors.
Crestani
F
F
Institute of Pharmacology and Toxicology, University of Zurich, Switzerland. crestani@pharma.unizh.ch
Martin
J R
JR
Möhler
H
H
Rudolph
U
U
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D003292:Convulsants / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000077334:Zolpidem
D000927:Anticonvulsants; D003292:Convulsants; D018756:GABA Antagonists; D006993:Hypnotics and Sedatives; D011725:Pyridines; D011963:Receptors, GABA-A; D000077334:Zolpidem; D003975:Diazepam; D010433:Pentylenetetrazole