Ethanol-induced inhibition of NMDA receptor channels

Ethanol is a potent inhibitor of the N-methyl-D-aspartate (NMDA)-receptor s ubtype of glutamate receptor in a number of brain areas. The mechanism of e thanol action has been investigated by means of patch-clamp recording of io nic currents and fura-2 measurement of intracellular Ca2+ concentration in cell culture systems; the subunit composition of NMDA receptors and their i nfluence on the effect of ethanol was determined by molecular biology metho ds. Ethanol does not appear to interact with NMDA either at the glutamate r ecognition site of the receptor, or at any of the hitherto known multiple m odulatory sites, such as the glycine or polyamine site. Moreover, ethanol d oes not cause an open channel block by itself and fails to interact with Mg 2+ at the site where it causes open channel block. The ability of ethanol t o inhibit responses to NMDA is dependent on the subunit combination of NMDA receptors. The NR1/NR2A and NR1/NR2B combinations are preferentially sensi tive to ethanol inhibition. Chronic treatment with ethanol leads to an incr ease of the NMDA receptor number at the transcriptional and posttranscripti onal level; the receptor function is also facilitated. This causes withdraw al-type seizures after termination of chronic treatment with ethanol. The i nhibition of NMDA receptors by ethanol leads to the depression of excitator y synaptic potentials mediated by this type of excitatory amino acid recept or. Ethanol-induced disturbances in certain regions of the brain, i.e. hipp ocampus, nucleus accumbens or locus coeruleus may lead to cognitive disorde rs or drug dependence. Brain slices containing the locus coeruleus may be u sed as an in vitro test system to investigate the addictive properties of e thanol. (C) 1999 Elsevier Science Ltd. All rights reserved.