Lithium-is-the-drug of choice in the treatment-of-bipolar- affective-disorder, although its mechanism of action remains unclear. Our major working hypothesis is that one effect of lithium is enhancement of CNS cholinergic activity. We have identified three potentially important effects of lithium and our goals are now to identify the mechanisms accounting for these effects. 1) Presynaptically, lithium enhances the synthesis and release of acetylcholine. We hypothesize that this is due to enhancement by lithium (i ) of intracellular calcium or (ii) of cyclic AMP, either of which enhances acetylcholine release. To test this hypothesis, we will measure the effects of lithium on calcium influx, efflux, sequestration and ATPase in synaptosomes. Second, we will measure the effects of lithium on cyclic AMP and cyclic AMP modulation of acetylcholine release. 2) We have found that chronic treatment with lithium depresses the muscarinic agonist-induced hydrolysis of phosphoinositides in rat cortical slices. We hypothesize that lithium reduces the response of this major second messenger-producing system by influencing either the receptor or the two primary second messengers, diacylglycerol and inositol trisphosphate. Therefore, we will measure the specificity of this effect and the effects of lithium on protein kinase C activity and inositol polyphosphate metabolism. 3) Lithium potentiates the in vivo response of the CNS to the muscarinic agonist, pilocarpine, as seen by the seizures generated by these two drugs. We have hypothesize that both presynaptic and postsynaptic effects of lithium play a role in this response. Presynaptic effects are discussed in #1 above and postsynaptic effects in #2 above. We will continue to test our major hypothesis by investigating whether lithium potentiates the effects of other cholinomimetics, including arecoline, physostigimine (an inhibition of acetylcholinesterase) and carbachol, an agonist which stimulates a much greater response by the phosphoinositide system than does pilocarpine. These studies are designed to test the hypothesis that lithium enhances cholinergic activity in the brain and to test the stated hypotheses as to the specific mechanisms of these effects of lithium. Attainment of these goals will increase our understanding of the effects of lithium that may be related to its therapeutic effect in mania and may generate hypotheses as to the underlying causes of bipolar affective disorders.
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