DEPRESSION--PSYCHOPATHOLOGY BEYOND THE RECEPTORS

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DESCRIPTION (Adapted from applicant's abstract): Depression is a common but complex disorder. Prior research suggests that impairments may exist in central beta adrenoceptor-linked mechanisms. The investigator intends to investigate processes beyond the noradrenergic beta receptor that may mediate these impairments. In a preliminary study, he has evaluated the activity of beta adrenoceptor-linked cAMP-dependent PKA in 12 persons with MDD and 10 normal controls in cultured fibroblast samples obtained by skin biopsy. Fibroblasts were chosen because they are readily available stem cells that display the beta-adrenoceptor signal transduction cascade of interest to the project. The data indicate that persons with MDD have substantially reduced basal and cAMP-stimulated PKA activity. Further, there is a reduction in PKA-mediated phosphorylation activity stimulated by the beta adrenoceptor signal transduction cascade of interest to the project. The data indicate that persons with MDD have substantially reduced basal and cAMP-stimulated PKA activity. Further, there is a reduction in PKA-mediated phosphorylation activity stimulated by the beta adrenoceptor agonist ISO. He proposes to confirm these findings in a larger sample of depressives and controls. Specifically, the goals of this application are to: 1) Recruit and very carefully diagnose a group of 50 persons with DSM-IV MDD (melancholic subtype) (by SCID-P and SADS-L) and 50 normal controls; 2) Obtain skin biopsies for fibroblast cell culture; 3) Evaluate differences between MDD and normal control groups in basal and cAMP-stimulated activity of PKA (as measured by the phosphorylation of the PKA substrate Kemptide); and 4) Assess the functional significance of any abnormalities in PKA by measuring the activation of PKA activity by the beta adrenoceptor agonist ISO and contrasting MDD and control groups. This project will determine whether persons with MDD display impairments in the beta adrenoceptor-second messenger transduction cascade at the level of PKA.