The N-methyl-D-aspartate (NMDA) receptor-induced inhibition of muscarinic receptor-stimulated phosphoinositide turnover in guinea pig cerebral cortical slices was investigated to determine whether polyamines regulate the function of NMDA in this system. None of the polyamines tested produced significant stimulation of phosphoinositide turnover. Neither spermine nor the substituted polyamine philanthotoxin-343 altered the inhibitory effect of NMDA. The simpler substituted polyamines N-(4-hydroxyphenylpropanoyl)-spermine and N-(4-hydroxyphenylacetyl)-spermine, however, antaganised the NMDA receptor inhibition of the muscarinic response with low affinity (Ki greater than or equal to 100 microM). Diethylenetriamine, a purported polyamine antagonist of the NMDA receptor, was without effect on the NMDA inhibitory response, as was ifenprodil, a structurally unrelated compound with reported antagonist capacity. In summary, therefore, we fail to observe polyamine regulation of the NMDA receptor mediating an inhibition of the muscarinic phosphoinositide turnover response in guinea pig cerebral cortical slices.