Persistent reduction of GABA(A) receptor-mediated inhibition in rat hippocampus after chronic intermittent ethanol treatment.
GABA(A) receptor-mediated function was studied in rats treated with chronic intermittent ethanol (CIE). Rats were given 60 doses of 6g/kg ethanol every 24 h by gastric intubation, with repeated intoxicating and withdrawal episodes leading to a kindling-like increase in seizure susceptibility (Kokka et al., Alcohol: Clin. Exp. Res., 17 (1993) 525-531). Efflux of 36Cl-, evoked by application of muscimol, a measure of GABA(A) receptor function, was examined in 300 mu m slices obtained from frontal, parietal, and temporal cortex, hippocampus, and inferior colliculus, one day after the last administration of ethanol. Compared to controls, the 36Cl- efflux in hippocampal slices of CIE rats was significantly reduced by 29%, while there were no changes in the other brain regions studied. In hippocampal slices, paired-pulse inhibition in CA1 pyramidal neurons, measured extracellularly using homosynaptic orthodromic stimulation at an interval of 10 ms, was significantly reduced in CIE rats. A significant decrease by 40% both at 2 and 40 days after 60 doses of ethanol was found, implying a persistent decrease in GABA(A) receptor-mediated inhibition in CIE rats. These reductions in paired-pulse inhibition are consistent with the decrease in the pentylenetetrazol (PTZ) seizure threshold which was previously observed in CIE rats. Therefore, we suggest that this reduction of GABA(A) receptor-mediated inhibition contributes to the persistent increase in seizure susceptibility of CIE rats.
Kang
M
M
Department of Molecular and Medical Pharmacology, School of Medicine, University of California, Los Angeles, CA 90024-1735, USA.
Spigelman
I
I
Sapp
D W
DW
Olsen
R W
RW
D000818:Animals; D001921:Brain / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D004334:Drug Administration Schedule; D004558:Electric Stimulation; D004594:Electrophysiology; D000431:Ethanol / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology*; D012016:Reference Values; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000503:physiopathology; D014018:Tissue Distribution
D002712:Chlorides; D018755:GABA Agonists; D011963:Receptors, GABA-A; D009118:Muscimol; D000431:Ethanol