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

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 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 non-selective and selective BZ-site agonists in squirrel monkeys. (triazolam, alprazolam, diazepam, 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"). Methods-Multiple doses of non-selective BZsResults-Administration of all BZ-type drugs resulted in ataxic-like and myorelaxant-like effects. Pretreatment with the α1 subunit-preferring antagonist βCCT (β-carboline-3-carboxylate-tbutyl ester) 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. KeywordsAtaxia; Myorelaxation; Motor impairment; Benzodiazepine; GABA A receptor; Monkey Benzodiazepines (BZs) are among the most widely prescribed drugs worldwide. These drugs produce their pharmacological effects by allosterically modulating the inhibitory action of γ-aminobutyric acid (GABA) at the GABA A receptor (for review, see Möhler 2006;Whiting 2006). Although the GABA A receptor is a pentameric structure formed by the assembly of NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript subunits from at least five different families (α 1-6 , β 1-3 , γ 1-3 , ρ 1-2 , and δ 1 ), only the α, β, and γ subunits are necessary to confer BZ sensitivity (McKernan and Whiting 1996;. Moreover, the behavioral effects of BZs appear to depend upon the presence of a particular α subunit. In this respect, GABA A receptors containing α1 subunits (α1GABA A receptors) have been proposed to mediate the sedative-like effects of BZs (Rudolph et al. 1999;McKernan et al. 2000). In contrast, the α2 and/or α3-containing GABA A receptors (α2GABA A , α3GABA A receptors) may be the substrates for the anxiolytic and myorelaxant effects of BZs (Rudolph et al. 1999;Löw et al. 2000;McKernan et al. 2000;Collins et al. 2002;Dias et al. 2005), while α5-containing receptors (α5GABA A receptors) may be involved in processes associated with memory (Collinson et al. 2002;Crestani et al. 2002).In general, the motor...

Assessment of subunit-dependent direct gating and allosteric modulatory effects of carisoprodol at GABAA receptors

“…Others have demonstrated muscle relaxation is associated preferentially with α2- and α3-expressing receptors (Crestani et al, 2001; Griebel et al, 2003; Licata et al, 2005; Licata et al, 2009). Although carisoprodol did not selectively interact with these subunits, it had notable allosteric modulatory effects on both α2- and α3-expressing receptors and almost similar potency for direct activation for α2-containing receptors as compared to most abundant configuration of human CNS, α1-containing receptors (Olsen and Sieghart, 2008).…”

The role of α1 and α5 subunit-containing GABAA receptors in motor impairment induced by benzodiazepines in rats

“…they induce ataxia, which is together with myorelaxation often referred to as motor impairment (Verster et al 2002; Licata et al 2009). In contrast to ataxia, myorelaxation can be therapeutically desirable, and disentangling the molecular substrates of these two effects would benefit the development of compounds with an improved pharmacological profile.…”

Effects of the benzodiazepine GABAA α1-preferring antagonist 3-isopropoxy-β-carboline hydrochloride (3-ISOPBC) on alcohol seeking and self-administration in baboons

“…Much work remains to understand this observation. Nevertheless, the real strength of the use of α1-preferring antagonists in the treatment of alcohol use disorder stems from the fact that this type of ligand lacks sedating, amnesic, and ataxic properties (Ator et al, 2010; Licata et al, 2009) because it is an antagonist at this α1 benzodiazepine GABA A site.…”

“…It is clear from the work of Licata et al (2009) in primates, June et al (2003) and Harvey et al (2002) in rodents, and Platt et al (2002) in rhesus macaques, that both βCCT and 3-PBC have been shown to be α1-preferring antagonists in vivo. Moreover, both βCCT and 3-PBC have been shown to be potent antagonists in vitro (Harvey et al, 2002; Yin et al, 2010).…”