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AL Morrow, PD Suzdak, JW Karanian and SM Paul
Section on Molecular Pharmacology, National Institute of Mental Health, Bethesda, Maryland.
The effect of chronic ethanol exposure on the function of the gamma- aminobutyric acid (GABA) receptor-coupled chloride ion channel was studied in synaptoneurosomes from rat cerebral cortex. Ethanol was administered to rats by inhalation resulting in high blood ethanol levels which have previously been shown to produce tolerance and dependence. After 14 days of ethanol exposure, the stimulation (apparent Vmax) of 36Cl- uptake by the GABA agonist muscimol was decreased by approximately 26%. Similarly, stimulation of 36Cl- uptake by the barbiturate pentobarbital was also reduced to the same extent and there was an increase in the apparent EC50 concentration. Direct stimulation of 36Cl- uptake by ethanol was unchanged after chronic ethanol exposure when measured in the same membrane preparations in which a decrease in muscimol and pentobarbital-stimulated 36Cl- uptake were observed. However, ethanol's ability to potentiate muscimol- stimulated 36Cl- uptake was abolished completely in synaptoneurosomes from ethanol-treated rats. The decrease in GABA receptor-coupled chloride ion channel function observed after chronic ethanol administration was observed only in animals where the mean blood ethanol concentration was greater than or equal to 150 mg%. These blood levels have previously been shown to be associated with ethanol withdrawal after ethanol discontinuation in this rat strain. Four days after ethanol administration, after all signs of ethanol withdrawal had subsided, the decrease in muscimol and pentobarbital-stimulated 36Cl- uptake was reversed. These data suggest that subsensitivity of the GABA receptor-coupled chloride ion channel after chronic ethanol administration may contribute to ethanol tolerance and the ethanol withdrawal syndrome.
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