Contribution of α1 subunit-containing γ-aminobutyric acidA (GABAA) receptors to motor-impairing effects of benzodiazepines in squirrel monkeys

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Abstract
Rationale Benzodiazepines (BZs) are effective anxiolytics and hypnotics, but their use is limited by unwanted side effects, such as motor impairment. Objectives To assess the contribution of α1 subunit-containing γ-aminobutyric acidA (GABAA) 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. Materials and methods Multiple doses of nonselective BZs (triazolam, alprazolam, diazepam, and chlordiazepoxide) and α1 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 α1 subunit-preferring antagonist β-carboline-3-carboxylate-t-butyl ester (βCCT) attenuated the ataxic-like effects engendered by both types of drugs. However, βCCT 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 α1 subunit-containing receptors in the alteration of hind-limb flexion, a putative measure of myorelaxation, induced by BZ-type drugs in monkeys.