FUNCTIONAL-CHARACTERIZATION OF A KINDLING-LIKE MODEL OF ETHANOL WITHDRAWAL IN CORTICAL CULTURED NEURONS AFTER CHRONIC INTERMITTENT ETHANOL EXPOSURE

Chronic ethanol exposure has been reported to alter NMDA and GABA(A) r eceptor function and gene expression in brain regions of animals and m ammalian cultured cortical neurons. In the present study, we investiga ted the effects of another model of chronic, but intermittent, ethanol treatment (CIE) on GABA(A) and NMDA receptor systems in cortical neur ons. CIE (50 mM ethanol, 12 h exposure/12 h withdrawal, 5 cycles) expo sure produced increased [H-3]MK-801 binding and diazepam insensitive b inding sites as measured by [H-3]Ro15-4513 binding to cortical culture d neuronal membranes, at 0 h following the last treatment cycle relati ve to control neurons. The NMDA mediated increase in intracellular cal cium [Ca-2+](i) was also increased following similar CIE treatment. CI E treatment also increased the ability of pentylenetetrazol (PTZ) to i nhibit GABA mediated Cl-36(-) influx relative to control neurons. Thes e effects were not reversible following 1 week ethanol withdrawal, imp lying enhanced sensitivity of PTZ to inhibit GABA(A) receptor mediated inhibition, and an increased NMDA receptor function in CIE treated co rtical neurons. These alterations are consistent with the behavioral s tudies in animals, and suggest that both GABA(A) and NMDA receptors pl ay an important role in ethanol withdrawal following either chronic or CIE exposure. Furthermore. this provides a feasible in vitro model fo r further biochemical and molecular studies of the mechanism underlyin g the CIE induced kindling-like phenomenon observed in humans. (C) 199 7 Elsevier Science B.V.