Ethanol effects on GABA-gated current in a model of increased alpha4betadelta GABAA receptor expression depend on time course and preexposure to low concentrations of the drug.

Several recent studies have suggested that alphabetadelta subtypes of gamma-aminobutyric acid type A (GABAA) receptors (delta-GABAR) are a target for low dose ethanol (<30 mM). However, there are also conflicting reports suggesting that only high doses of the drug (100 mM) modulate these receptors. In addition, the studies which have demonstrated a clear effect of low dose ethanol on delta-GABAR find different effective concentrations for this effect. Here, we test the hypothesis that the apparent disparity in effective concentration is due to time-course effects when low (1-3 mM) dose ethanol is preapplied. To this end, we tested ethanol effects on native GABAR in CA1 hippocampus in a model of increased alpha4betadelta GABAR expression following 48h administration of the GABA-modulatory steroid THP (3alpha-OH-5beta-pregnan-20-one) to adult, female rats. GABA(EC20)-gated current was recorded with whole-cell patch clamp procedures from acutely isolated pyramidal cells. We assessed ethanol's effect on GABA-gated current using either (1) 2-5 min application of ethanol in increasing concentrations (0.1-30 mM) or (2) coadministration of ethanol with GABA. Two minute application of 1-3 mM ethanol produced optimal potentiation of GABA-gated current following steroid treatment, with higher concentrations less effective. In contrast, 30 mM ethanol produced optimal effects when ethanol was not preapplied. However, following preapplication of 1mM ethanol, 30 mM ethanol decreased the peak GABA-gated current. These findings suggest that ethanol may act at multiple interacting sites to affect GABAR efficacy and desensitization. These data also suggest that ethanol effects on GABA-gated current are affected by the time course of exposure and previous exposure to low concentrations of the drug.