The role of alpha(1) and alpha(5) subunit-containing GABA(A) receptors in motor impairment induced by benzodiazepines in rats

Abstract

Benzodiazepines negatively affect motor coordination and balance and produce myorelaxation. The aim of the present study was to examine the extent to which populations of gamma-aminobutyric acid A (GABA(A)) receptors containing alpha(1) and alpha(5) subunits contribute to these motor-impairing effects in rats. We used the nonselective agonist diazepam and the alpha(1)-selective agonist zolpidem, as well as nonselective, alpha(1)-subunit and alpha(5)-subunit-selective antagonists flumazenil, beta CCt, and XLi093, respectively. Ataxia and muscle relaxation were assessed by rotarod and grip strength tests performed 20 min after intraperitoneal treatment. Diazepam (2 mg/kg) induced significant ataxia and muscle relaxation, which were completely prevented by pretreatment with flumazenil (10mg/kg) and beta CCt (20 mg/kg). XLi093 antagonized the myorelaxant, but not the ataxic actions of diazepam. All three doses of zolpidem (1, 2, and 5 mg/kg) produced ataxia, but only the highest dose (5 mg/kg) significantly decreased the grip strength. These effects of zolpidem were reversed by beta CCt at doses of 5 and 10 mg/kg, respectively. The present study demonstrates that alpha(1) GABA(A) receptors mediate ataxia and indirectly contribute to myorelaxation in rats, whereas alpha(5) GABA(A) receptors contribute significantly, although not dominantly, to muscle relaxation but not ataxia. Behavioural Pharmacology 23:191-197