Contribution of alpha1 subunit-containing gamma-aminobutyric acidA (GABAA) receptors to motor-impairing effects of benzodiazepines in squirrel monkeys.
BACKGROUND
Benzodiazepines (BZs) are effective anxiolytics and hypnotics, but their use is limited by unwanted side effects, such as motor impairment.


OBJECTIVE
To assess the contribution of alpha1 subunit-containing gamma-aminobutyric acid(A) (GABA(A)) receptor subtypes to the motor-impairing effects of BZs, the present study evaluated two observable measures of motor coordination (balance on a pole, resistance to hind-limb flexion) engendered by nonselective and selective BZ-site agonists in squirrel monkeys.


METHODS
Multiple doses of nonselective BZs (triazolam, alprazolam, diazepam, and chlordiazepoxide) and alpha1 subunit-preferring agonists (zolpidem and zaleplon) were administered to adult male squirrel monkeys (N = 4-6), and experimenters rated the monkey's ability to balance on a horizontal pole ("ataxic-like effects"), as well as the degree of resistance to hind-limb flexion ("myorelaxant-like effects").


RESULTS
Administration of all BZ-type drugs resulted in ataxic-like and myorelaxant-like effects. Pretreatment with the alpha1 subunit-preferring antagonist beta-carboline-3-carboxylate-t-butyl ester (betaCCT) attenuated the ataxic-like effects engendered by both types of drugs. However, betaCCT was largely ineffective at blocking the ability of both BZs and non-BZs to induce myorelaxant-like effects.


CONCLUSIONS
These experiments demonstrate dose-dependent motor impairment in squirrel monkeys using quantitative behavioral observation techniques. Altogether, these findings suggest a lack of a prominent role for alpha1 subunit-containing receptors in the alteration of hind-limb flexion, a putative measure of myorelaxation, induced by BZ-type drugs in monkeys.
Licata
Stephanie C
SC
McLean Hospital/Harvard Medical School, Belmont, MA, USA.
Platt
Donna M
DM
Cook
James M
JM
Van Linn
Michael L
ML
Rowlett
James K
JK
D000818:Animals; D001259:Ataxia / Q000139:chemically induced* / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D011963:Receptors, GABA-A / Q000378:metabolism*; D012453:Saimiri
D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D001569:Benzodiazepines