The proposed research is in three areas: In the first we will determine the effect of lithium and classical cholinergic agonists and antagonists on myo-inositol, the myoinostol phosphates, and on the phosphoinositides and related metabolites. We are interested in the changes in levels of these substances and on the turnover of the phosphoinositides and related lipid products. Our objective is to determine the range of the effect of lithium on inositol metabolism because of the potential value of lithium as a tool for studying the phosphoinositides, and because of its pharmocological effectiveness and toxicity in the treatment of manic depressive disease. We will examine these effects mainly in rat cerebral cortex and synaptosomes but additionally in other organs of the rat. The second area is collaborative work studying the levels of myo-inositol, scylloinositol, fructose and sorbitol in sural nerve biopsy samples from healthy and diabetic patients. This work is an effort to determine if changes in the tissue levels of these substances are related to neuropathy. In a second collaborative project we are measuring the levels and microregional distribution of myo-inositol in cochlear nucleus. This is a survey study to determine areas in the nervous system with relative dependence/independence on inositols. The third area is in the study of the distribution and enzymology of three mammalian enzymes of inositol metabolism: L-myo-inositol 1-phosphate synthase, L-myo-inositol 1-phosphate phosphatase and the inositol epimerase. The phosphatase is of interest both because of its role in inositol metabolism and because it is strongly inhibited by lithium, which may account for part of its role in vivo. The synthase is the key enzyme for all inositol de novo synthesis; little is known of its regulation, more needs to be known about its mechanism. The mammalian inositol epimerase has never been isolated before. It is responsible for scyllo-inositol synthesis and thus may reveal the role of this inositol in tissues. The mechanism, regulation and distribution of each of these enzymes will be studied to increase our knowledge of inositol metabolism in vivo.