The role of α1 and α5 subunit-containing GABAA receptors in motor impairment induced by benzodiazepines in rats.
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 γ-aminobutyric acid A (GABAA) receptors containing α1 and α5 subunits contribute to these motor-impairing effects in rats. We used the nonselective agonist diazepam and the α1-selective agonist zolpidem, as well as nonselective, α1-subunit and α5-subunit-selective antagonists flumazenil, βCCt, 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 (10 mg/kg) and βCCt (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 βCCt at doses of 5 and 10 mg/kg, respectively. The present study demonstrates that α1 GABAA receptors mediate ataxia and indirectly contribute to myorelaxation in rats, whereas α5 GABAA receptors contribute significantly, although not dominantly, to muscle relaxation but not ataxia.
Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
Marija
M
Milić
Jovana
J
Divljaković
Sundari
S
Rallapalli
Michael L
ML
van Linn
Tamara
T
Timić
James M
JM
Cook
Miroslav M
MM
Savić
D000818:Animals; D001259:Ataxia / Q000139:chemically induced / Q000503:physiopathology*; D001569:Benzodiazepines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology; D003975:Diazepam / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005442:Flumazenil / Q000494:pharmacology; D058785:GABA-A Receptor Agonists / Q000494:pharmacology / Q000502:physiology*; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D018737:Hand Strength / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology*; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000502:physiology*; D045442:Rotarod Performance Test / Q000379:methods; D000077334:Zolpidem
C480603:1,3-bis(8-ethynyl-5,6-dihydro-5-methyl-6-oxo-4H-imidazo(1,5-a)(1,4)benzodiazepine-3-carboxy)propyl diester; D001570:Benzodiazepinones; D002243:Carbolines; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; C546242:Gabra1 protein, rat; C511535:Gabra5 protein, rat; D007093:Imidazoles; D011725:Pyridines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005442:Flumazenil; D000077334:Zolpidem; C043232:tert-butyl beta-carboline-3-carboxylate; D003975:Diazepam