We plan to extend our understanding of the acute and chronic effects of lithium on the metabolism of the phosphoinositides.
The research aims to evaluate four propositions: 1) As a result of the uncompetitive inhibition of myo-inositol-1-phosphatase (M1P'ase) by lithium, which traps myo-inositol in myo-inositol-1-phosphate (M1P), thereby reducing cellular inositol levels, the metabolism of one or more of the phosphoinositides is altered. This alteration results in significant effects on receptor metabolism and basal cellular metabolism. 2) Lithium potentiates the response of muscarinic cholinergic receptors and other types of receptors by a mechanism independent of its M1P'ase inhibition. 3) Reduced myo-inositol levels and increased receptor activation persist on chronic administration of lithium. 4) Lithium is a useful tool for identifying the activation of receptors that respond via phosphoinositide metabolism. The first three hypotheses may have relevance for the understanding of mechanisms by which lithium functions in the treatment of affective disorder. By means of lesioning experiments we will try to determine if the basis of lithium's apparent muscarinic cholinergic action is enhancement of endogenous cholinergic activity. Through kinetic experiments on cerebral cortex slices we will determine if lithium potentiates receptor response to agonists. We will conduct studies in brain slices and in vivo to determine in what way phosphoinositide metabolism is being altered by lithium. These studies will employ radiosotope uptake and loss in response to stimulation and will be carried out on a time scale of seconds to minutes and by using experiments designed to stress the responsive systems to their limits. Studies will be carried out to determine whether adaptive changes in inositol metabolism occur on chronic lithium administration, including studies on changes in levels and activity of the enzymes L-myo-inositol-1-phosphate synthase and M1P'ase. Because the lithium inhibition of M1P'ase allows ready analysis of receptor-activated phosphatidylinositol metabolism (and perhaps polyphosphoinositide metabolism) we will explore the utility of lithium as a tool for the identification of metabolism involving these receptors.
