In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 102, No. 3 ( 2005-01-18), p. 915-920
Abstract:
Benzodiazepines exert their effects by binding to multiple subtypes of the GABA A receptor, the predominant subtypes in the brain being those that contain α 1 -, α 2 -, α 3 -, and α 5 -subunits. To understand the potentially different roles of these subtypes in the therapeutic and side effects of benzodiazepines, we evaluated GABA A receptor subtype-preferring compounds in nonhuman primate models predictive of anxiolytic, sedative, motor, subjective, and reinforcing effects of benzodiazepine-type drugs. These compounds included zolpidem, which shows preferential binding to GABA A receptors containing α 1 -subunits (α 1 GABA A receptors); L-838,417, which shows functional selectivity for α 2 GABA A , α 3 GABA A , and α 5 GABA A receptors; and nonselective conventional benzodiazepines. The results provide evidence in nonhuman primates that α 1 GABA A receptors do not play a key role in the anxiolytic and muscle-relaxant properties of benzodiazepine-type drugs; instead, these effects involve α 2 GABA A , α 3 GABA A , and/or α 5 GABA A subtypes. Our results also suggest that the α 1 GABA A receptor subtype might be critically involved in the subjective, sedative, and motor effects of benzodiazepine-type drugs. In contrast, stimulation of α 1 GABA A receptors is sufficient, but not necessary, for mediation of the abuse potential of these drugs.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.0405621102
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2005
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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