Different GABAA receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates.
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.
Rowlett
James K
JK
Harvard Medical School, New England Primate Research Center, One Pine Hill Road, Box 9102, Southborough, MA 01772, USA. james.rowlett@hms.harvard.edu
Platt
Donna M
DM
Lelas
Snjezana
S
Atack
John R
JR
Dawson
Gerard R
GR
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001259:Ataxia / Q000139:chemically induced; D001569:Benzodiazepines / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008253:Macaca mulatta; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D011963:Receptors, GABA-A / Q000145:classification / Q000378:metabolism / Q000502:physiology*; D012453:Saimiri; D019966:Substance-Related Disorders / Q000209:etiology*
D014151:Anti-Anxiety Agents; D021122:Protein Subunits; D011963:Receptors, GABA-A; D001569:Benzodiazepines