Pharmacological studies over the past two decades have established acute actions of lithium on post-receptor targets in the brain. Lithium has been shown to inhibit adenylate cyclase (the enzyme that synthesizes cyclic AMP) and certain inositol phosphatases [involved in the phosphatidylinositol (PI) cycle] and to disrupt G-protein function. However, these acute effects cannot per se explain the therapeutic actions of lithium which require its chronic administration, and much less is known about the more long lasting changes that chronic exposure to lithium induces in brain. Although there have been a number of studies on the effects of chronic lithium on the cyclic AMP and PI systems, these investigations have been difficult to interpret mechanistically in that most reflect indirect measures of proteins which can be affected by many factors. The proposed pharmacological and neurochemical studies will directly examine the effects of chronic lithium and other antidepressant treatments on individual protein components of G-proteins and the cyclic AMP pathway to obtain a better understanding of drug action. In preliminary studies, we have shown that chronic lithium increases levels of mRNA and immuno-reactivity of type 1 and type 2 adenylate cyclase, and decreases levels of mRNA and immunoreactivity of the G- protein subunits, Gialpha1 and Gialpha2. These effects where observed under """"""""therapeutic"""""""" conditions (i.e., 4 weeks of treatment with serum lithium levels of about 1 mM), but not in response to short-term treatment or to chronic treatment with a lower dose of lithium. These intracellular adaptations would be expected to result in an up-regulated cyclic AMP system and could represent a homeostatic response to acute lithium inhibition of adenylate cyclase. In addition, we have found that chronic lithium alters the subcellular distribution of cyclic AMP- dependent protein kinase in rat cortex, with an apparent translocation of the lithium-induced alterations in the phosphorylation state of a number of specific phosphoproteins, including DARPP-32, a dopamine and cyclic AMP-regulated phosphoprotein of 32 kD. Similar effects were seen with certain other antidepressant treatments, but not with other classes of psychotropic drugs. The purpose of the proposed studies is to further characterize lithium and antidepressant regulation of these and related intracellular messengers with respect to the time course, dose dependence, and pharmacological and anatomical specificity of drug action. The proposed investigations, aimed at characterizing lithium- and antidepressant-induced adaptations in intracellular signal transduction pathways in rat brain, will provide a more complete understanding of the pharmacological and neurochemical actions exerted by long-term exposure to these drugs of the brain.
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