Benzodiazepine actions mediated by specific γ-aminobutyric acid(A) receptor subtypes

Uwe Rudolph, Florence Crestani, Dietmar Benke, Ina Brünig, Jack A. Benson, Jean Marc Fritschy, James R. Martin, Horst Bluethmann, Hanns Möhler

Research output: Contribution to journalArticlepeer-review


GABA(A) (γ-aminobutyric acid(A)) 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 GABA(A) receptors, which are mainly expressed in cortical areas and thalamus, 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 GABA(A) receptors found in the limbic system (α2, α5), in monoaminergic neurons (α3) and in motoneurons (α2, α5). Thus, benzodiazepine-induced behavioural responses are mediated by specific GABA(A) receptor subtypes in distinct neuronal circuits, which is of interest for drug design.

Original languageEnglish (US)
Pages (from-to)796-800
Number of pages5
Issue number6755
StatePublished - Oct 21 1999
Externally publishedYes

ASJC Scopus subject areas

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