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Different GABAA receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2005 Jan 18; Vol. 102 (3), pp. 915-20. Date of Electronic Publication: 2005 Jan 11. - Publication Year :
- 2005
-
Abstract
- Benzodiazepines exert their effects by binding to multiple subtypes of the GABAA receptor, the predominant subtypes in the brain being those that contain alpha1-, alpha2-, alpha3-, and alpha5-subunits. To understand the potentially different roles of these subtypes in the therapeutic and side effects of benzodiazepines, we evaluated GABAA 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 GABAA receptors containing alpha1-subunits (alpha1GABAA receptors); L-838,417, which shows functional selectivity for alpha2GABAA, alpha3GABAA, and alpha5GABAA receptors; and nonselective conventional benzodiazepines. The results provide evidence in nonhuman primates that alpha1GABAA receptors do not play a key role in the anxiolytic and muscle-relaxant properties of benzodiazepine-type drugs; instead, these effects involve alpha2GABAA, alpha3GABAA, and/or alpha5GABAA subtypes. Our results also suggest that the alpha1GABAA receptor subtype might be critically involved in the subjective, sedative, and motor effects of benzodiazepine-type drugs. In contrast, stimulation of alpha1GABAA receptors is sufficient, but not necessary, for mediation of the abuse potential of these drugs.
- Subjects :
- Animals
Anti-Anxiety Agents administration & dosage
Ataxia chemically induced
Benzodiazepines administration & dosage
Dose-Response Relationship, Drug
Female
Macaca mulatta
Male
Muscle Relaxation drug effects
Protein Subunits metabolism
Receptors, GABA-A classification
Receptors, GABA-A metabolism
Saimiri
Anti-Anxiety Agents pharmacology
Benzodiazepines pharmacology
Motor Activity drug effects
Receptors, GABA-A physiology
Substance-Related Disorders etiology
Subjects
Details
- Language :
- English
- ISSN :
- 0027-8424
- Volume :
- 102
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 15644443
- Full Text :
- https://doi.org/10.1073/pnas.0405621102