Lithium is one of the most effective psychopharmacological treatments, yet the mechanism of its action remains unknown. Recent studies have demonstrated a site of action for lithium in inositol lipid metabolism in the central nervous system. Hydrolysis of the phosphoinositides is also a principal molecular event mediating the cellular response and long-term regulation of several neurotransmitter receptors, including the muscarinic receptor. Central muscarinic activity has been shown to be associated with a state-independent clinical predisposition to recurrent affective episodes. Extended clinical treatment with lithium reduces the vulnerability to recurrent affective episodes. We propose that long-term adaptive changes in essential elements of muscarinic receptor regulation may contribute to this clinical therapeutic effect. The net result of lithium's action on muscarinic receptor activity may stem not only from direct action on the muscarinic/phosphoinositide (PI) response system, but also from indirect effects on other neurotransmitter-coupled PI systems influencing cholinergic activity in specific regions of the brain. Thus, this proposal intends to focus upon the effects of chronic lithium on the regulation of the muscarinic receptor in the limbic system of animals undergoing selective pharmacological/behavioral treatment strategies. These strategies are designed to affect central muscarinic response in ways that are consistent with current clinical concepts regarding predisposition to mania/depression and the primary therapeutic actions of lithium. Alterations in receptor responsivity may take place at any one or all levels of the receptor response complex. Therefore, our experimental design will examine the muscarinic receptor response, in accordance with previous studies in our laboratory, at three critical levels of function: a) binding properties of muscarinic-receptor subtypes; b) muscarinic agonist-coupled PI response; and c) associated changes in protein kinase C activity. Receptor-coupled biochemical events in limbic regions of the brain represent potential sites for a substantial modification of cellular/physiological/behavioral function. These long-term alterations are both potent, by virtue of the generated intracellular signals, and specific, by virtue of the selective receptor-subtypes involved. It is expected that these investigations will provide basic knowledge regarding the mechanism of action of lithium in the treatment of recurrent affective illness and lead to a better understanding of the neurobiological basis of this disorder.
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