A Comparison of the Effects of Ethanol and the Competitive Glycine Antagonist 7‐Chlorokynurenic Acid on N ‐Methyl‐ d ‐Aspartic Acid‐Induced Neurotransmitter Release from Rat Hippocampal Slices

N ‐Methyl‐ d ‐aspartate (NMDA; 500 μ M ) stimulated the net release of preloaded tritiated norepinephrine from rat hippocampal slices. Both ethanol and the competitive glycine antagonist 7‐chlorokynurenic acid (7‐CK) dose‐dependently inhibited NMDA‐stimulated release without affecting basal, nonstimulated efflux. These inhibitory effects were readily reversed upon washout of the drugs. Over the concentration range tested (25–200 m M ), ethanol inhibited ∼65% of NMDA‐stimulated release with an estimated IC 50 of ∼70 m M . In contrast, 7‐CK fully inhibited release (>95%) at a concentration of 30 μ M with half‐maximal inhibition occurring at ∼2 μ M . The combination of 7‐CK (1–30 μ M ) and ethanol (25–100 m M ) had an additive inhibitory effect on NMDA‐stimulated release but did not alter the inhibitory potency of 7‐CK. Calculated IC 50 values for 7‐CK in the presence of 25, 50, or 100 m M ethanol were (mean × SEM; μ M ) 2.33 (0.11), 2.38 (0.23), and 1.99 (0.30), respectively. 7‐CK (3 μ M ) inhibited NMDA‐stimulated [ 3 H]norepinephrine release by ∼50%. This inhibition was fully attenuated by the addition of the glycine agonistserine with complete reversal occurring at 30 μ M d ‐serine. Increasing the 7‐CK concentration to 10 μ M shifted the d ‐serine dose‐effect curve to the right in a parallel fashion as expected for a competitive antagonist. In contrast, the inhibitory effects of ethanol or the combination of 7‐CK (3 μ M ) and ethanol (25 or 50 m M ) were not reversed by the addition of d ‐serine (0.1–1,000 μ M ). Together, these results suggest that ethanol's inhibition of NMDA‐stimulated [ 3 H]norepinephrine release from hippocampal slices is not due to a simple competitive interaction with the glycine site on the NMDA receptor.