Protein kinase C (PKC) activity and PKC translocation in response to serotonin were investigated in platelets obtained from bipolar affective disorder subjects before and during lithium treatment. Ratios of platelet membrane-bound to cytosolic PKC activities were elevated in the manic subjects. In addition, serotonin-elicited platelet PKC translocation was found to be enhanced in those subjects. Lithium treatment for up to 2 weeks resulted in a reduction in cytosolic and membrane-associated PKC activities and in an attenuated PKC translocation in response to serotonin. These preliminary results suggest that alteration in platelet PKC is associated with the manic phase of bipolar illness. The results also suggest that lithium treatment reduces the sensitivity of platelets to PKC translocation induced by activation of serotonin-2 receptors.