Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes.
GABA(A) (gamma-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 alpha1-subunit gene, that alpha1-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 gamma-aminobutyric acid is preserved. alpha1(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 (alpha2, alpha5), in monoaminergic neurons (alpha3) and in motoneurons (alpha2, alpha5). Thus, benzodiazepine-induced behavioural responses are mediated by specific GABA(A) receptor subtypes in distinct neuronal circuits, which is of interest for drug design.
Rudolph
U
U
Institute of Pharmacology, University of Zürich, Switzerland. rudolph@pharma.unizh.ch
Crestani
F
F
Benke
D
D
Brünig
I
I
Benson
J A
JA
Fritschy
J M
JM
Martin
J R
JR
Bluethmann
H
H
Möhler
H
H
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology; D001120:Arginine / Q000378:metabolism; D001569:Benzodiazepines / Q000378:metabolism / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology*; D015195:Drug Design; D018757:GABA Modulators / Q000494:pharmacology*; D006639:Histidine / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D017354:Point Mutation; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D009125:Muscle Relaxants, Central; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D006639:Histidine; D001120:Arginine; D003975:Diazepam