Ethanol enhances [3H]diazepam binding at the benzodiazepine-gamma-aminobutyric acid receptor-ionophore complex
Davis, W.C.; Ticku, M.K.
Molecular Pharmacology 20(2): 287-294
1981
ISSN/ISBN: 0026-895X PMID: 6272088 Document Number: 171394
Ethanol, which has a pharmacological profile similar to those of barbiturates and benzodiazepines, enhances [3H]diazepam binding to the crude Lubrol-solubilized fraction from rat brain. This fraction had specific binding sites for [3H]diazepam, [3H]muscimol and [.alpha.-3H]dihydropicrotoxinin (DHP). Ethanol enhanced [3H]diazepam to this fraction in a dose-dependent manner with a maximal enhancement of 90 .+-. 8.5% occurring at 100 mM and a half-maximal effect occurring at 30 mM. Ethanol (100 mM) changed the Kd from a control value of 9.36 .+-. 126 to 4.40 .+-. 0.33 nM (P > 0.005). The Bmax (maximum binding) of [3H]diazepam binding was not significantly altered. The enhancing effect of ethanol was blocked by picrotoxinin and (+)-bicuculline. Ethanol, while enhancing [3H]diazepam binding to the crude Lubrol fraction, partially inhibited the binding of [3H]DHP and had no effect on [3H]muscimol binding. The rank order of enhancement of [3H]diazepam binding with various alcohols (ethanol > methanol > isopropyl alcohol > propanol-1 = t-butyl alcohol = butanol-1) did not agree with their partition coefficients. Ethanol, like pentobarbital, may enhance [3H]diazepam binding at the benzodiazepine-GABA receptor-ionophore complex. This interaction will result in facilitation of GABAergic transmission and may be responsible for some of the central effects of alcohol, such as antianxiety, muscle relaxant and sedative. Ethanol does not enhance [3H]diazepam directly at the benzodiazepine binding site, but rather indirectly via the picrotoxinin-sensitive site of the benzodiazepine-GABA receptor-ionophore complex.