A series of short chain alkanols were studied for their effects on N-methyl-D-aspartate (NMDA)-evoked release [3H]norepinephrine (NE) from slices of cortex of the rat. Methanol, ethanol, isopropanol, n-propanol, n-butanol and isoamyl alcohol inhibited NMDA-stimulated release of [3H]NE in a concentration-dependent manner, while having no effect on non-stimulated release of [3H]NE. The inhibitory potencies of the alkanols varied with the shorter chain alkanols, such as methanol, being less potent than the longer chain alkanols, such as isoamyl alcohol. Direct comparison of the effects of 100 mM methanol, ethanol, isopropanol, n-propanol and n-butanol indicated that increasing the chain length led to a greater efficacy for producing inhibition of NMDA-stimulated release of [3H]NE. A plot of the log IC50 values, versus the log of the membrane/buffer partition coefficients for the various alkanols was linear, indicating that lipophilicity played some role in the inhibitory effect. The alkanols did not significantly depress the release of [3H]NE stimulated by 25 mM KCl, in the presence of 300 microM 2-amino-5-phosphonopentanoic acid (AP-5), suggesting that the alkanols have a selective effect at the NMDA receptor, as opposed to altering the release of neurotransmitter at the nerve terminal. The inhibitory effects of the alcohols were reversible, which suggests that the alcohols were not causing non-specific toxic effects on the slices. It is concluded that the inhibitory effect of ethanol and related short chain alkanols on NMDA-stimulated release of [3H]NE involves an interaction with a lipophilic target, at or near the NMDA receptor-ionophore complex.