Recent literature and our previous observations indicated the presence of both NMDA and serotonin type 3 receptors in human platelets with very similar ionic currents to that of cultured mammalian neuronal receptors. Baseline electrophysiological data shows similar profile for platelets from both normal and schizophrenic subjects, whereas serotonin receptor studies exhibited the presence of 5-hydroxytryptamine type-3 (5-HT3) currents in both normal and schizophrenic platelets significantly different from each other. The two major differences observed were: first, 5-HT3 receptors present in the platelets of schizophrenic patients were four times more sensitive to serotonin than those present in the platelets of normal subjects and, second, that D: -serine in micro molar concentrations dampens this effect in platelets from schizophrenic patients but increases the sensitivity of serotonin for platelet 5-HT3 receptors of normal subjects. Patch clamp technique was used to measure the whole cell currents passing through serotonin receptors in these two types of human platelets. The currents were found to be 5-HT3 receptor currents as they were abolished by 10 microM D-tubocurarine. Similarly, micromolar concentrations of D: -serine increased the sensitivity of 5HT3 receptor currents in the normal human platelets but decreased it in the platelets of the schizophrenic patients. This effect was reversed when D-amino acid oxidase (0.3 microM) was co applied with 100 microM of D-serine, raising the possibility that D-serine by itself may act as a modulator for platelet 5-HT3 receptor channel currents. These observations raised exciting new questions about the role of platelet serotonin receptors and their regulation by D-serine.