Mechanism of action of the hypnotic zolpidem in vivo

Florence Crestani; James R. Martin; Hanns Möhler; Uwe Rudolph

doi:10.1038/sj.bjp.0703717

Mechanism of action of the hypnotic zolpidem in vivo

Florence Crestani, James R. Martin, Hanns Möhler, Uwe Rudolph

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Pages (from-to)	1251-1254
Number of pages	4
Journal	British Journal of Pharmacology
Volume	131
Issue number	7
DOIs	https://doi.org/10.1038/sj.bjp.0703717
State	Published - 2000
Externally published	Yes

Keywords

Benzodiazepines
GABA(A) receptor
Knock-in mouse
Targeted mutation
Zolpidem

ASJC Scopus subject areas

Pharmacology

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abstract = "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.",

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author = "Florence Crestani and Martin, {James R.} and Hanns M{\"o}hler and Uwe Rudolph",

year = "2000",

doi = "10.1038/sj.bjp.0703717",

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AU - Crestani, Florence

AU - Martin, James R.

AU - Möhler, Hanns

AU - Rudolph, Uwe

PY - 2000

Y1 - 2000

N2 - 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.

AB - 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.

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KW - GABA(A) receptor

KW - Knock-in mouse

KW - Targeted mutation

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Mechanism of action of the hypnotic zolpidem in vivo

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Keywords

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