Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 482, Issue 1-3, Pages 215-222Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2003.10.007
Keywords
cross-tolerance; ethanol; flunitrazepam; GABA(A) receptor; gaboxadol; THIP; hypnotic; rotarod; zolpidem; indiplon
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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 GABAA 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 3 1, 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. (C) 2003 Elsevier B.V. All rights reserved.
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