Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes

Uwe Rudolph (), Florence Crestani, Dietmar Benke, Ina Brünig, Jack A. Benson, Jean-Marc Fritschy, James R. Martin, Horst Bluethmann and Hanns Möhler
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Uwe Rudolph: Institute of Pharmacology, University of Zürich, and Swiss Institute of Technology (ETH)
Florence Crestani: Institute of Pharmacology, University of Zürich, and Swiss Institute of Technology (ETH)
Dietmar Benke: Institute of Pharmacology, University of Zürich, and Swiss Institute of Technology (ETH)
Ina Brünig: Institute of Pharmacology, University of Zürich, and Swiss Institute of Technology (ETH)
Jack A. Benson: Institute of Pharmacology, University of Zürich, and Swiss Institute of Technology (ETH)
Jean-Marc Fritschy: Institute of Pharmacology, University of Zürich, and Swiss Institute of Technology (ETH)
James R. Martin: Preclinical Research, F. Hoffmann-LaRoche Ltd
Horst Bluethmann: Preclinical Research, F. Hoffmann-LaRoche Ltd
Hanns Möhler: Institute of Pharmacology, University of Zürich, and Swiss Institute of Technology (ETH)

Nature, 1999, vol. 401, issue 6755, 796-800

Abstract: Abstract GABAA (γ-aminobutyric acidA) receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity and memory functions, which is evident from the spectrum of actions elicited by clinically effective drugs acting at their modulatory benzodiazepine-binding site. Here we show, by introducing a histidine-to-arginine point mutation at position 101 of the murine α1-subunit gene, that α1-type GABAA receptors, which are mainly expressed in cortical areas and thalamus1, are rendered insensitive to allosteric modulation by benzodiazepine-site ligands, whilst regulation by the physiological neurotransmitter γ-aminobutyric acid is preserved. α1(H101R) mice failed to show the sedative, amnesic and partly the anticonvulsant action of diazepam. In contrast, the anxiolytic-like, myorelaxant, motor-impairing and ethanol-potentiating effects were fully retained, and are attributed to the nonmutated GABAA receptors found in the limbic system (α2, α5), in monoaminergic neurons (α3) and in motoneurons (α2, α5)1. Thus, benzodiazepine-induced behavioural responses are mediated by specific GABAA receptor subtypes in distinct neuronal circuits, which is of interest for drug design.

Date: 1999
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DOI: 10.1038/44579

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