Ethanol inhibits glutamatergic neurotransmission in nucleus accumbens neurons by multiple mechanisms.

The nucleus accumbens (NAcc) likely plays a role in the rewarding effects of several addictive drugs such as opiates and EtOH. We showed previously that low EtOH concentrations reduced glutamatergic excitatory postsynaptic potentials (EP-SPs) in NAcc neurons. Naloxone inhibited this effect. In the present study we have begun characterizing the receptors 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-di-one-resistant EPSPs that were blocked by the N-methyl-D-aspartate (NMDA) receptor antagonist DL-2-amino-5-phosphonovalerate. In 6-cyano-7-nitroquinoxaline-2,3-dione (a non-NMDA glutamate receptor antagonist), EtOH 66 mM decreased these NMDA-EPSPs. Application of exogenous NMDA or non-NMDA [kainate, (R,S)-alpha-amino-3-hydroxy-5-methyli-soxazole-4-propionic acid or quisqualate] glutamate agonists evoked reversible depolarizations or inward currents. The NMDA-induced currents increased with membrane depolarization and were blocked by DL-2-amino-5-phosphonovalerate. EtOH 11 to 200 mM decreased the NMDA currents significantly and dose-dependently, without effect of naloxone. Higher EtOH concentrations (44-66 mM) also reduced slightly kainate-induced currents (again without a naloxone effect), but not (R,S)-alpha-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 reduce the EPSPs at normal resting potentials, but not responses to non-NMDA glutamate agonists, EtOH probably acts both pre- and postsynaptically: by an opioid-dependent reduction of glutamate release and by postsynaptically reducing NMDA and kainate currents. By virtue of the likely role NAcc plays in alcoholism, these actions could represent major determinants in the intoxicating and reinforcing properties of EtOH.