TY - JOUR
T1 - Benzodiazepine actions mediated by specific γ-aminobutyric acid(A) receptor subtypes
AU - Rudolph, Uwe
AU - Crestani, Florence
AU - Benke, Dietmar
AU - Brünig, Ina
AU - Benson, Jack A.
AU - Fritschy, Jean Marc
AU - Martin, James R.
AU - Bluethmann, Horst
AU - Möhler, Hanns
PY - 1999/10/21
Y1 - 1999/10/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0033592682&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0033592682&partnerID=8YFLogxK
U2 - 10.1038/44579
DO - 10.1038/44579
M3 - Article
C2 - 10548105
AN - SCOPUS:0033592682
SN - 0028-0836
VL - 401
SP - 796
EP - 800
JO - Nature
JF - Nature
IS - 6755
ER -