ANTIDEPRESSANTS: SIGNAL TRANSDUCTION AND GENE EXPRESSION

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Major depressive illness is alleviated by chronic but not acute administration of antidepressant drugs or electroconvulsive therapy. Although the biochemical mechanisms of antidepressant action are not clearly understood, the delay in the therapeutic efficacy of these treatments has led to the hypothesis that some adaptive alteration in neuronal function must occur over time. The most consistent adaptive- biochemical effect of chronic antidepressant treatment in experimental animals is a down-regulation of the B-adrenergic receptor (BAR)-coupled adenylate cyclase system. This system is also regulated by pituitary- adrenal hormones and clinical investigations have indicated that there is a dysfunction of this hormone system in many depressed patients. Taken together these findings suggest that a pituitary-adrenal hormone imbalance may contribute to the biochemical alterations which underlie depression. The long-term objective of this research proposal is to extend previous work beyond the level of receptor binding sites and second messengers by studying antidepressant and pituitary-adrenal hormone regulation of BARs and G proteins at the level of gene expression. The regulation of BARs and G protein messenger RNA by antidepressant and hormone treatment will be determined by Northern blot analysis using specific cDNA probes while the levels of G protein subunits will be studied by quantitative immunolabeling and ADP- ribosylation. Preliminary studies have demonstrated that chronic imipramine treatment regulates the level of BAR mRNA while both antidepressant and glucocorticoid administration differentially regulate the levels of message and protein for specific G protein subunits. These effects will be further investigated and extended to an examination of their time dependence, pharmacology and regional specificity and the rate of gene transcription will be directly examined by nuclear runoff assays. Finally, neurotransmitter receptor-G protein regulation of adenylate cyclase will be studied to access the physiological relevance of the antidepressant and hormone induced alterations. These studies could elucidate the adaptive-molecular mechanisms which mediate antidepressant therapy as well as the role of pituitary-adrenal hormones in the etiology of depression.