BRAIN NEURONAL DEGENERATION CAUSED BY EPISODIC ALCOHOL-INTOXICATION IN RATS - EFFECTS OF NIMODIPINE, 6,7-DINITRO-QUINOXALINE-2,3-DIONE, ANDMK-801

Rats repeatedly intoxicated with alcohol (ethanol, three times daily) over a 4-day period display neuronal degeneration in the dentate gyrus ; entorhinal, piriform, insular, orbital, and perirhinal cortices; and in the olfactory nerve fibers and terminals in the olfactory bulb. Po stulating a role for excitotoxicity, we have attempted to prevent the degeneration using antagonists that are neuroprotective in this type o f brain damage. In an initial study, continuous subcutaneous infusion of a high dose of the glutamate/NMDA receptor antagonist MK-801 (2 mg/ kg/day) by itself caused extensive neuronal degeneration in several br ain regions and severe behavioral intoxication that precluded survival a combined with high blood alcohol levers (similar to 300 mg/dl). Mor eover, the lower, nonneurotoxic blood alcohol levels (similar to 150 m g/dl) that were compatible with survival worsened the MK-801-induced b rain damage. In a subsequent experiment, daily intraperitoneal injecti ons of a lower dose of MK-801 (1 mg/kg/day) resulted in no MK-801 toxi city and, when combined with neurotoxic levels of alcohol, no reductio n in alcohol-induced neurotoxicity. Nimodipine, a voltage-gated Ca2+ c hannel blocker, reduced the neuronal damage in the dentate gyrus, but greatly increased it in the piriform cortex when administered intragas trically at 600 mg/kg/day; it provided no protection from alcohol-depe ndent degeneration when given intragastrically at 100 mg/kg/day. Conti nuous intracerebroventricular delivery of 0.24 to 0.29 mg/day of 6,7-d initro-quinoxaline-2,3-dione, a utamate/alpha-amino-3-hydroxy-5-methyl -4-isoxazole receptor antagonist, failed to diminish alcohol-dependent neuronal damage in any brain region. We conclude that brain damage fr om episodic ''binge'' alcohol intoxication is not primarily mediated b y excitotoxic mechanisms, implying that other, nonexcitotoxic pathophy siological mechanisms, are involved. Furthermore, MK-801, far from pro tecting from the alcohol-induced damage, at high doses causes widespre ad neuropathology that is significantly potentiated by alcohol.