PROTEIN KINASE C IN MANIA & IN LITHIUM'S ACTIONS

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Lithium's clinical utility in treating affective disorders is well established. However, the relevant pharmacological mechanism(s) for these actions of the ion have not been elucidated. Numerous previous reports have described the effects of lithium on various serotonergic and other neurotransmitter mechanisms. Recent investigations have suggested that the clinical effects of lithium may be mediated by the ion's ability to inhibit the dephosphorylation of inositol-1-phosphate and thus antagonize phosphatidylinositol hydrolysis which is a signal transduction system shared by various neurotransmitters and hormones. Investigations performed in our laboratory have documented the effect of lithium on brain serotonin release and on the role of protein kinase C (PKC) in modulating serotonin release. In preliminary studies, we have observed that lithium can inhibit (1) PKC-stimulated serotonin release in brain and platelets and (2) PKC stimulation induced translocation of the enzyme in brain and platelets. These studies also indicate that platelet PKC subcellular distribution and manic patients are markedly different from controls. In the proposed investigation, we plan to (1) examine platelet serotonin release and irs modulation by PKC stimulation in patients with affective disorders, (2) measure platelet protein kinase C activity, its subcellular distribution and its response to serotonergic and other stimuli in subjects diagnosed as having affective disorders, and (3) examine the relationship between clinical response to lithium and its effects on the above platelet serotonin and PKC markers. The studies aim to (1) explore the possibility that PKC is a biological marker for mania and (2) test the hypothesized relationship between lithium's therapeutic action in affective disorders and its effects on phosphorylation mediated by PKC.