In the present study, infrared differential interference contrast videomicroscopy was used to examine the effect of histamine on N-methyl-D-aspartate-induced swelling in neostriatal neurons in a brain slice preparation. Histamine caused a concentration-dependent increase in swelling evoked by N-methyl-D-aspartate. By itself, histamine did not cause swelling. Electrical stimulation also caused N-methyl-D-aspartate-dependent swelling which was enhanced by histamine. In addition, histamine was found to enhance N-methyl-D aspartate-induced swelling from postnatal day 7 to 28 but not at postnatal day 3. Finally, this histamine-induced enhancement was prevented by treatment with either the H2 receptor antagonist cimetidine or with the potassium channel blocker tetraethylammonium chloride. Overall, these findings suggest that histamine modulates N-methyl-D-aspartate receptor function in the neostriatum through a H2 receptor-mediated regulation of potassium channels.