Spermidine reverses arcaine's inhibition of N-methyl-D-aspartate-induced hippocampal [³H]norepinephrine release

The inhibition of N-methyl-D-aspartate (NMDA)-induced [³H]norepinephrine ([³HNE) release by a putrescine analog was studied. We report that arcaine, diguanidinobutane, a putative competitive polyamine antagonist, completely and noncompetitively antagonized NMDA-induced [³H]NE release from rat hippocampal minces with an IC₅₀ value of 102 μM. Arcaine did not alter kainate- or potassium-induced [³H]NE release suggesting a specific effect on NMDA-mediated responses. Spermidine did not alter NMDA-induced [³H]NE release, nor did it reverse the effect of arcaine when introduced in a normal physiologic superfusion buffer. However, spermidine reversed the effect of arcaine when superfusing with buffer that contained 5% (v/v) of the organic solvent dimethylsulfoxide. This finding suggests that the polyamine site may be located at the intracellular surface of the cell membrane. Our results provide the first evidence for polyamine modulation of the NMDA receptor ionophore complex in a functional physiologic system.