Our results suggest that the PKA pathway may participate in ethanol-induced neurobehavioral changes and that NMDA receptors may be involved in the PKA regulation of ethanol's actions.
1 N-methyl-D-aspartate (NMDA) receptors have been demonstrated to be a pivotal target for ethanol action. The present study examined the actions of acute ethanol exposure on NMDA-induced responses and the acute tolerance to ethanol actions in rat sympathetic preganglionic neurons (SPNs) in vitro and in vivo. 2 NMDA (50 mM) applied every 5 min induced reproducible membrane depolarizations of SPNs in neonatal spinal cord slice preparations. Ethanol (50 -100 mM) applied by superfusion for 15 min caused a sustained decrease in NMDA-induced depolarizations in a dose-dependent and reversible manner. When the superfusion time of ethanol (100 mM) was increased to 50 min, NMDA-induced depolarizations were attenuated initially but a gradual recovery was seen in B40% of SPNs tested. 3 Repeated injections of NMDA (2 nmol) intrathecally at 30 min interval caused reproducible increases in mean arterial pressure (MAP) in urethane-anesthetized rats. Intravenous injections of ethanol (0.16 or 0.32 g, 1 ml) inhibited NMDA-induced pressor effects in a blood concentrationdependent manner. The inhibition by ethanol of NMDA-induced pressor effects was reduced over time during continuous infusion of ethanol or on the second injection 3.5 h after prior injection of a higher dose of ethanol. 4 Ethanol, at concentrations significantly inhibited NMDA-induced responses, had no significant effects on a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced responses. The study demonstrated the selective inhibition by ethanol of NMDA-induced responses and the development of acute tolerance to the inhibitory effects in SPNs both in vitro and in vivo. These effects may play important roles in the ethanol regulation of cardiovascular function.
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