ETHANOL INHIBITS THE N-METHYL-D-ASPARTATE (NMDA)-INDUCED ATTENUATION OF THE NMDA-EVOKED NORADRENALINE RELEASE IN THE RAT-BRAIN CORTEX - INTERACTION WITH NMDA-INDUCED DESENSITIZATION

The influence of ethanol, AP5 (DL-2-amino-5-phosphonopentanoic acid) and dizocilpine (MK-801) ((+)-5-methyl-10, 11-dihydro-5H-dibenzo (a,b)-cyclohept-5,10-imine hydrogen maleate) on the NMDA-induced attenuation of the NMDA-evoked noradrenaline release was examined in rat brain cortex slices preincubated with H-3-noradrenaline. The slices were superfused with Mg2+-free Krebs-Henseleit solution. Tritium overflow (corresponding to H-3-noradrenaline release) was stimulated by 300-mu-mol/l NMDA for 2 min. Presence of 10-100-mu-mol/l NMDA from 20 to 2 min before stimulation concentration-dependently inhibited the NMDA (300-mu-mol/l)-evoked H-3 overflow, suggesting an agonist-induced desensitization attributable to the modification of events at the NMDA receptor itself and/or distal to this receptor system. The desensitizing effect of 100-mu-mol/l NMDA was almost complete and was not diminished when the time of preexposure was decreased to 10 min, and when NMDA was removed from the superfusion fluid for up to 5 min before the stimulus; however, the densitizing effect was reduced after further decrease in the duration of preexposure to NMDA or further prolongation of the interval between preexposure and stimulation. Ethanol inhibited the NMDA-induced H-3 overflow (IC50 45 mmol/l; this effect was almost abolished when ethanol was omitted from the superfusion fluid from 2 min before stimulation onward. Ethanol, when simultaneously present with 100-mu-mol/l NMDA in the superfusion fluid from 20 to 2 min before the NMDA stimulus, concentration-dependently (IC50 112 mmol/l) decreased the inhibitory effect of NMDA. The effect of ethanol was identical to that of the competitive NMDA receptor antagonist AP5 both with respect to the rapid reversibility of the inhibition of NMDA-induced H-3 overflow (i.e. within 2 min) and to the decrease of the desensitizing effect of NMDA. The pattern of effects obtained with dizocilpine, an inhibitor of the ion channel coupled to the NMDA receptor, was different from that obtained with ethanol and AP5: the inhibitory effect of dizocilpine on the NMDA-evoked H-3 overflow was only partly reversible within 8 min after withdrawal, and the inhibitory effect of NMDA on NMDA-evoked H-3 overflow was not decreased by dizocilpine, but was more pronounced than with either NMDA or dizocilpine alone. It is concluded that ethanol mimics AP5 in that in inhibits the NMDA-induced desensitization, possibly by preventing the NMDA receptor from being activated by NMDA applied during the desensitization period. In contrast, dizocilpine produces no such effect. The potency of ethanol in inhibiting the NMDA-induced desensitization was about 3 times less than in inhibiting NMDA-evoked noradrenaline release. These results are compatible with the suggesting that the NMDA recognition site itself may be one of the sites of action of ethanol and that ethanol does not modify the function of the NMDA receptor system by a machanism comparable to that of dizocilpine.