The long-term goals of this application are 1) To test the hypothesis that down-regulation of central beta adrenoceptors in the high agonist affinity conformation, coupled to adenylate cyclase, is a common biological action of all clinically effective antidepressant treatments. 2) To pharmacologically characterize the serotonin/norepinephrine linked beta adrenoceptor system in brain by establishing competition binding curves and subjecting them to nonlinear regression analysis under various experimental conditions. 3) To understand the complex aminergic and endocrine regulation and expression of central beta adrenoceptor systems. Using combined pharmacological and molecular biological approaches, the action of drugs which either alleviate or precipitate depressive reactions in man will be studied on beta adrenoceptor gene transcription in vitro (C6 glioma cell cultures) and in brain in vivo in the normal rat and in rats with selective lesions of serotonergic neurons. The regional distribution and ontogenesis of beta adrenoceptor gene expression in brain will be determined by using synthetic oligodeoxynucleotide or the nick- translated beta adrenoceptor cDNA as hybridization probes. Experiments are proposed to ascertain whether tricyclics could modify beta adrenoceptor mediated preproenkephalin gene expression in brain and thus fine-tune the availability of enkephalins in brain areas relevant to modd and pain. To study the role of the """"""""serotonin/norepinehprine/glucocorticoid link"""""""" of the beta adrenoceptor coupled adenylate cyclase system in preproenkephalin gene expression, the preproenkephalin message will be studied following selective lesions of serotonergic neurons and following bilateral adrenalectomy. Since ECT is probably the most efficacious treatment of severe depression, experiments are proposed to study if ECT wil modify - like antidepressant drugs - beta adrenoceptor and preproenkephalin gene transcription in brain and whether or not the onset of such changes will be more rapid. To study the location of cell populations that express the beta adrenoceptor mRNA in brain, in situ hybridization experiments are planned. Since the serotonin/norepinephrine linked beta adrenoceptor coupled adenylate cyclase system in brain is proposed to function as an amplification/adaptation system of sensory information processing, a better understanding of its regulation and expression is relevant to an understanding of the pharmacotherapy and pathophysiology of affective disorders.
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