Chronic ethanol exposure leads to a selective enhancement of N-methyl-D-aspartate receptor function in cultured hippocampal neurons.
Effects of chronic ethanol exposure on N-methyl-D-aspartate (NMDA) receptor function were examined in hippocampal neurons. Rat hippocampal neurons grown in culture were chronically exposed to 100 mM ethanol to examine mechanisms that could underlie ethanol-induced changes in receptor function and excitotoxicity. NMDA-stimulated, but not kainic acid-stimulated, increases in intracellular calcium were enhanced after 1-, 2- and 7-day exposures to 100 mM ethanol. Chronic exposure to ethanol for 7 days duration increased the magnitude of cell death mediated by NMDA application, but not that mediated by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate or kainic acid exposure. In addition, NMDA-induced excitotoxicity after chronic ethanol exposure (CEE) was not altered in the presence of nifedipine. The enhancement of NMDA-induced neuronal cell death was evident after 2 days of CEE, but not significantly different after a 1-day exposure to 100 mM ethanol. The enhancement of NMDA-induced calcium responses and excitotoxicity could be mimicked by a chronic 7-day exposure to aminophosphonovaleric acid. However, a concomitant chronic exposure of ethanol/aminophosphonovaleric acid did not enhance NMDA-induced calcium responses or excitotoxicity. Chronic exposure paradigms did not consistently alter basal intracellular calcium levels nor total cell number in the absence of exposure to glutamate receptor agonist. These findings support the hypothesis that NMDA receptor function is enhanced after CEE, and this predisposes hippocampal neurons to excitotoxicity.
Smothers
C T
CT
Department of Anatomy and Physiology, Vanderbilt University Medical School, Nashville, Tennessee 37232-0615, USA.
Mrotek
J J
JJ
Lovinger
D M
DM
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects*; D016202:N-Methylaspartate / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000502:physiology
D015220:Calcium Channels; D016194:Receptors, N-Methyl-D-Aspartate; D000431:Ethanol; D016202:N-Methylaspartate; D002118:Calcium