CHRONIC ETHANOL TREATMENT UP-REGULATES THE NMDA RECEPTOR FUNCTION ANDBINDING IN MAMMALIAN CORTICAL-NEURONS

In the present study, we investigated the effects of chronic ethanol e xposure on NMDA-mediated increase in intracellular calcium concentrati on ([Ca2+](i)) by means of fluorescent measurement of [Ca2+](i) with F ura-2AM in mammalian cortical cultured neurons, and the radioligand [H -3]MK-801 binding to cortical neuronal membranes. Chronic exposure of the cortical neurons to ethanol (50 mM, 5 days) did not produce any ch ange in the cell protein, morphological appearance, and the resting [C a2+](i); however, it significantly enhanced the NMDA-mediated increase in [Ca2+](i). The EC(50) value of NMDA was not significantly altered following chronic ethanol exposure, however, its E(max) value was incr eased by similar to 45%. Furthermore, chronic ethanol exposure increas ed the specific [H-3]MK-801 binding in cortical neuronal membrane prep aration by similar to 30%. The enhancement of the NMDA-mediated increa se in [Ca2+](i) and the increase in [H-3]MK-801 specific binding were reversed following 48 h ethanol withdrawal. Additionally, this enhance d NMDA response and the increased [H-3]MK-801 specific binding were su sceptible to blockade by the concomitant chronic exposure of the corti cal neurons to the NMDA receptor competitive (20 mu M CPP), and non-co mpetitive (1 mu M MK-801) antagonists, but not by the non-NMDA recepto r antagonist, CNQX (10 mu M), and the L-type calcium channel blocker, nitrendipine (10 mu M). Taken together, these results suggest that chr onic ethanol exposure upregulated the NMDA receptor function and bindi ng in cortical cultured neurons, and this increased NMDA receptor func tion is a NMDA receptor-mediated process. This altered NMDA receptor f unction may be responsible for the chronic ethanol-induced behavioral consequences and withdrawal syndrome associated with chronic ethanol e xposure.