Chronic ethanol intoxication induces differential effects on GABAA 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 (GABAA) 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-[35S]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 35S-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 In contrast, ethanol-withdrawn rats tested at 9 to 24 hr showed a dramatic enhancement in their sensitivity to the convulsant action of isoniazid (50 to 250 mg/kg, sc).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 micrograms/5 microliters/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.(ABSTRACT TRUNCATED AT 250 WORDS)
Sanna
E
E
Department of Experimental Biology, University of Cagliari, Italy.
Serra
M
M
Cossu
A
A
Colombo
G
G
Follesa
P
P
Cuccheddu
T
T
Concas
A
A
Biggio
G
G
D000430:Alcohol Withdrawal Delirium / Q000503:physiopathology; D000437:Alcoholism / Q000503:physiopathology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology; D001643:Bridged Bicyclo Compounds / Q000493:pharmacokinetics; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels; D003292:Convulsants / Q000493:pharmacokinetics / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics; D000431:Ethanol / Q000633:toxicity*; D007538:Isoniazid / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000502:physiology; D016202:N-Methylaspartate / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000502:physiology; D012640:Seizures / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels; D003292:Convulsants; D008565:Membrane Proteins; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; C037476:tert-butylbicyclophosphorothionate; D007608:Kainic Acid; D007538:Isoniazid