Benzodiazepine agonist and inverse agonist actions on GABAA receptor-operated chloride channels. II. Chronic effects of ethanol.
Mice were made tolerant to and dependent on ethanol by administration of a liquid diet. Gamma-aminobutyric acid (GABA) receptor-dependent uptake of 36Cl- by mouse cortical microsacs was used to study the actions of benzodiazepine (BZ) agonists and inverse agonists. Chronic exposure to ethanol attenuated the ability of a BZ agonist, flunitrazepam, to augment muscimol-stimulated uptake of 36Cl- and enhanced the actions of BZ inverse agonists, Ro15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,4]-benzodiazepine - 3-carboxylate) and DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate), to inhibit GABAA receptor-operated chloride channels. Augmentation of chloride flux by pentobarbital was not reduced by chronic ethanol exposure. Attenuation of flunitrazepam efficacy was transient and returned to control levels within 6 to 24 hr after withdrawal from ethanol, but increased sensitivity to Ro15-4513 was observed as long as 8 days after withdrawal. Chronic exposure to ethanol did not alter [3H]SR 95531 ([2-(3'-carbethoxy-2'propyl)-3-amino-6-p-methoxyphenylpyridazinium bromide] binding to low-affinity GABAA receptors or muscimol stimulation of chloride flux; and did not alter [3H]Ro15-4513 or [3H]flunitrazepam binding to central BZ receptors or allosteric modulation of this binding by muscimol (i.e., muscimol-shift). These results suggest that chronic exposure to ethanol reduces coupling between BZ agonist sites and the chloride channel, and may be responsible for the development of cross-tolerance between ethanol and BZ agonists. In contrast, coupling between BZ inverse agonist sites and the chloride channel is increased.(ABSTRACT TRUNCATED AT 250 WORDS)
Buck
K J
KJ
Department of Pharmacology, University of Colorado Health Sciences Center, Denver.
Harris
R A
RA
D000818:Animals; D001386:Azides / Q000378:metabolism / Q000494:pharmacology*; D001569:Benzodiazepines / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002243:Carbolines / Q000378:metabolism / Q000494:pharmacology*; D018118:Chloride Channels; D002712:Chlorides / Q000378:metabolism*; D003292:Convulsants / Q000378:metabolism / Q000494:pharmacology*; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D005445:Flunitrazepam / Q000378:metabolism / Q000494:pharmacology*; D018756:GABA Antagonists; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D011724:Pyridazines / Q000378:metabolism; D011963:Receptors, GABA-A / Q000187:drug effects*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D014316:Tritium
D001386:Azides; D002243:Carbolines; D018118:Chloride Channels; D002712:Chlorides; D003292:Convulsants; D018756:GABA Antagonists; D008565:Membrane Proteins; D011724:Pyridazines; D011963:Receptors, GABA-A; D014316:Tritium; D001569:Benzodiazepines; C034818:methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate; D000431:Ethanol; D005445:Flunitrazepam; C042957:Ro 15-4513; C049853:gabazine