GABA-A Alpha-2 Receptor Subunit Proposed as Target for Antianxiety Drugs
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WESTPORT, CT (Reuters Health) Oct 9 - The alpha-2 subtype of gamma-aminobutyric acid type A (GABA-A) receptors mediates the anxiety-relieving effects of benzodiazepines in mice, according to a report in the October 6th issue of Science.
The researchers explain that although they previously linked the sedative and amnesic properties of diazepam to alpha-1 GABA-A receptors, until now it was not possible to identify the GABA-A receptor subtypes that mediate the drug's anxiolytic effects.
Dr. Karin Low, currently at the University of California at San Diego, and colleagues studied the behavioral and physiological effects of diazepam-insensitive mutations in GABA-A receptor subtypes alpha-2 and alpha-3 in mice.
Diazepam-insensitive binding sites increased from 5% in wild-type mice to 17% in alpha-2 mutant mice and 11% in alpha-3 mutant mice, the authors report. The potentiation by diazepam of the normal electrophysiological response to GABA-A was diminished in cultured mouse hippocampal pyramidal cells bearing the alpha-2 mutation.
Diazepam's sedative, motor-impairing, and anticonvulsant effects were retained in both alpha-2 and alpha-3 mutant mice, the researchers note.
In two behavioral tests, alpha-2 mutant mice failed to show the anxiolytic-like effect of diazepam treatment, the investigators observed. Alpha-3 mutant mice and wild-type mice, in contrast, displayed the usual dose-dependent anxiolytic-like response to diazepam.
"The anxiolytic-like action of diazepam is selectively mediated by the enhancement of GABAergic transmission in a population of neurons expressing the alpha-2 GABA-A receptors, which represent only 15% of all diazepam-sensitive GABA-A receptors," the authors conclude. "Our findings indicate that the alpha-2 GABA-A receptors are highly specific targets for the development of future selective anxiolytic drugs."
Science 2000;290:131-134. |
