Rotarod studies in the rat of the GABAA receptor agonist gaboxadol: lack of ethanol potentiation and benzodiazepine cross-tolerance.
All benzodiazepines and benzodiazepine site agonists impair motor performance dose-dependently and potentiate the effects of ethanol. In order to evaluate the risk of benzodiazepine and ethanol interaction with the direct acting GABA(A) receptor agonist 4,5,6,7-tetrahydroisoxazolo (5,4-c) pyridin-3-ol (gaboxadol), we studied impairment of motor coordination for combinations of gaboxadol, ethanol and a series of benzodiazepines (flunitrazepam, zolpidem and indiplon) in a rat rotarod model. All compounds produced a dose-dependent motor impairment and, in agreement with earlier data, a supra-additive effect of the benzodiazepine ligands and ethanol 1 g/kg was seen. In contrast, no significant potentiation of the effects of gaboxadol by ethanol was detected, and furthermore, no synergistic interaction between gaboxadol and any of the benzodiazepines was seen. A 30-day tolerance study was conducted with daily injections of gaboxadol (7.9 mg/kg) and zolpidem (1.25 mg/kg), respectively. A time-dependent tolerance developed to the motor impairment produced by both compounds. On day 31, cross-tolerance studies between zolpidem/gaboxadol and gaboxadol/zolpidem were conducted. No cross-tolerance was observed, indicating that the motor coordination effects observed with gaboxadol and zolpidem may arise from interaction with different receptor populations.
Voss
Jeppe
J
Department of Neuropharmacology, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark.
Sanchez
Connie
C
Michelsen
Signe
S
Ebert
Bjarke
B
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004361:Drug Tolerance / Q000502:physiology; D000431:Ethanol / Q000494:pharmacology*; D018755:GABA Agonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000502:physiology; D045442:Rotarod Performance Test / Q000379:methods*
D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D007555:Isoxazoles; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D000431:Ethanol; C015542:gaboxadol