Chronic Ethanol Intoxication Induces Differential Effects on GABAA and NMDA Receptor Function in the Rat Brain

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Abstract
The effect of long-term treatment with ethanol was investigated on the function of γ-aminobutyric acid A (GABAA) and N-methyl-d-as-partic 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-[36S]Butylbicyclophosphorothionate (35S-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 36Cl-uptake and its enhancement by flunitrazepam was decreased in the ethanol-treated animals. 35S-TBPS binding and 36Cl-influx measured 9 to 24 hr following the last ethanol injection, when withdrawal signs were present, were unmodified with respect to saline-treated rats. Moreover, the effects of both isoniazid and FG 7142 on 36S-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 In contrast, ethanol-withdrawn rats tested at 9 to 24 hr showed a dramatic enhancement in their sensitivity to the convulsant action of isoniazid (50 to 250 mg/kg, sc).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 μg/5 μl/rat intracerebroventricularly) and kainic acid (12 mg/kg, ip), and this effect was paralleled by an enhancement (+25%) in the density of 3H-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 3H-MK 801 binding in the hippocampl of ethanol-dependent rats compared with controls. These results indicate that, in contrast to acute administration, chronic ethanol intoxication may lead to a reduction of GABAA 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 3H-MK 801 binding sites. The latter finding strongly suggests that a functional activation of glutamatergic synapses, rather than a decrease in GABAA receptor function, is a crucial event during ethanol withdrawal.