Molecular and neuronal substrate for the selective attenuation of anxiety.
Benzodiazepine tranquilizers are used in the treatment of anxiety disorders. To identify the molecular and neuronal target mediating the anxiolytic action of benzodiazepines, we generated and analyzed two mouse lines in which the alpha2 or alpha3 GABAA (gamma-aminobutyric acid type A) receptors, respectively, were rendered insensitive to diazepam by a knock-in point mutation. The anxiolytic action of diazepam was absent in mice with the alpha2(H101R) point mutation but present in mice with the alpha3(H126R) point mutation. These findings indicate that the anxiolytic effect of benzodiazepine drugs is mediated by alpha2 GABAA receptors, which are largely expressed in the limbic system, but not by alpha3 GABAA receptors, which predominate in the reticular activating system.
Löw
K
K
Institute of Pharmacology and Toxicology, University of Zürich, and Swiss Federal Institute of Technology Zürich (ETH), Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
Crestani
F
F
Keist
R
R
Benke
D
D
Brünig
I
I
Benson
J A
JA
Fritschy
J M
JM
Rülicke
T
T
Bluethmann
H
H
Möhler
H
H
Rudolph
U
U
D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003975:Diazepam / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D018390:Gene Targeting; D006624:Hippocampus / Q000166:cytology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018408:Patch-Clamp Techniques; D010634:Phenobarbital / Q000494:pharmacology; D017354:Point Mutation; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D014151:Anti-Anxiety Agents; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D003975:Diazepam; D010634:Phenobarbital