CHRONIC ETHANOL INTOXICATION INDUCES DIFFERENTIAL-EFFECTS ON GABA-A AND NMDA RECEPTOR FUNCTION IN THE RAT-BRAIN

The effect of long-term treatment with ethanol was investigated on the function of gamma-aminobutyric acid A (GABA(A)) and N-methyl-d-aspartic acid (NMDA) receptors. Rats were rendered ethanol-dependent by repeated forced administration of a 20% ethanol solution (12 to 18 g/kg/day po) for 6 days and tested while still intoxicated or at different time intervals after withdrawal. t-[S-35]Butylbicyclophosphorothionate (S-35-TBPS) binding was increased by 30% in cortical homogenates of rats killed 1 to 3 hr after last ethanol administration, when compared with saline-treated animals. However, GABA-stimulated Cl-36- uptake and its enhancement by flunitrazepam was decreased in the ethanol-treated animals. S-35-TBPS binding and Cl-36-influx measured 9 to 24 hr following the last ethanol injection, when withdrawal signs were present, were unmodified with respect to saline-treated rate. Moreover, the effects of both isoniazid and FG 7142 on S-35-TBPS binding were unchanged in ethanol-dependent rats tested at 1 to 3 and 9 to 24 hr, compared with controls. In contrast, ethanol-withdrawn rats tested at 9 to 24 hr showed a dramatic enhancement in their sensitivity to the convulsant action of isoniazid (50 to 250 mg/kg, sc). The same animals were also more susceptible to the convulsant action of NMDA (0.5 to 5 mug/5 mul/rat intracerebroventricularly) and kainic acid (12 mg/kg, ip), and this effect was paralleled by an enhancement (+25%) in the density of H-3-MK 801 recognition sites in the hippocampus. The increased pharmacological response to both isoniazid and excitatory amino acids was no longer detectable as early as 3 to 6 days of ethanol withdrawal, when most of the withdrawal signs disappeared. Moreover, 6 days after withdrawal we observed a significant reduction of H-3-MK 801 binding in the hippocampi of ethanol-dependent rats compared with controls. These result indicate that, in contrast to acute administration, chronic ethanol intoxication may lead to a reduction of GABA(A) receptor function, an effect no longer detectable during withdrawal. On the contrary, we found a good correlation between development of withdrawal symptoms and the increase in H-3-MK 801 binding sites. The latter finding strongly suggests that a functional activation of glutamatergic synapases, rather than a decrease in GABA(A) receptor function, is a crucial event during ethanol withdrawal.