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

Abstract

The effect of long‐term treatment with ethanol was investigated on the function of γ ‐aminobutyric acid A (GABA A ) 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 ‐[ 36 S]Butylbicyclophosphorothionate ( 35 S‐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 36 Cl‐uptake and its enhancement by flunitrazepam was decreased in the ethanol‐treated animals. 35 S‐TBPS binding and 36 Cl‐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 36 S‐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 In contrast, ethanol‐withdrawn rats tested at 9 to 24 hr showed a dramatic enhancement in their sensitivity to the convulsant action of isoniazid (50 to 250 mg/kg, sc).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 μ g/5 μ l/rat intracerebroventricularly) and kainic acid (12 mg/kg, ip), and this effect was paralleled by an enhancement (+25%) in the density of 3 H‐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 3 H‐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 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 3 H‐MK 801 binding sites. The latter finding strongly suggests that a functional activation of glutamatergic synapses, rather than a decrease in GABA A receptor function, is a crucial event during ethanol withdrawal.