The ability of polyamines to modulate N-methyl-D-aspartate (NMDA) receptor function was investigated in Xenopus oocytes injected with rat brain mRNA. Whereas spermine and spermidine augmented NMDA/glycine-induced inwards currents, arcaine (1,4-diguanidinobutane) and 1,10-diaminodecane inhibited the response. The potency of arcaine to inhibit NMDA/glycine-induced currents was unaffected by spermine; similarly, arcaine did not influence the potency of spermine, but did reduce the maximal response to spermine. These findings demonstrate that polyamines exert both positive and negative modulatory control of the NMDA receptor expressed in Xenopus oocytes, and suggest that spermine and arcaine act at distinct sites in the NMDA receptor complex.