ETHANOL INHIBITS GLUTAMATERGIC NEUROTRANSMISSION IN NUCLEUS-ACCUMBENSNEURONS BY MULTIPLE MECHANISMS

The nucleus accumbens (NAcc) likely plays a role in the rewarding effe cts of several addictive drugs such as opiates and EtOH. We showed pre viously that low EtOH concentrations reduced glutamatergic excitatory postsynaptic potentials (EP-SPs) in NAcc neurons. Naloxone inhibited t his effect. In the present study we have begun characterizing the rece ptors involved in the evoked EPSPs and examined the action of EtOH on these receptors by using intracellular recording (voltage- and current -clamp) in the rat NAcc slice. At depolarized membrane potentials, we found 6-cyano-7-nitroquinoxaline-2,3-dione-resistant EPSPs that were b locked by the N-methyl-D-aspartate (NMDA) receptor antagonist DL-2-ami no-5- phosphonovalerate. In 6-cyano-7-nitroquinoxaline-2,3-dione (a no n-NMDA glutamate receptor antagonist), EtOH 66 mM decreased these NMDA -EPSPs. Application of exogenous NMDA or non-NMDA [kainate, lpha-amino -3-hydroxy-5-methylisoxazole-4-propionic acid or quisqualate] glutamat e agonists evoked reversible depolarizations or inward currents. The N MDA-induced currents increased with membrane depolarization and were b locked by DL-2-amino-5-phosphonovalerate. EtOH 11 to 200 mM decreased the NMDA currents significantly and dose-dependently, without effect o f naloxone. Higher EtOH concentrations (44-66 mM) also reduced slightl y kainate-induced currents (again without a naloxone effect), but not lpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid or quisqualate currents. These data suggest that NAcc core neurons express both NMDA and non-NMDA glutamate receptors. Because low EtOH concentrations red uce the EPSPs at normal resting potentials, but not responses to,non-N MDA glutamate agonists, ROH probably acts both pre- and postsynaptical ly: by an opioid-dependent reduction of glutamate release and by posts ynaptically reducing NMDA and kainate currents. By virtue of the likel y role NAcc plays in alcoholism, these actions could represent major d eterminants in the intoxicating and reinforcing properties of EtOH.