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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH052339-02
Application #
2430977
Study Section
Clinical Neuroscience and Biological Psychopathology Review Committee (CNBP)
Project Start
1996-09-01
Project End
1999-05-31
Budget Start
1997-06-01
Budget End
1999-05-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Garbett, K A; Vereczkei, A; Kálmán, S et al. (2015) Fibroblasts from patients with major depressive disorder show distinct transcriptional response to metabolic stressors. Transl Psychiatry 5:e523
Garbett, Krassimira A; Vereczkei, Andrea; Kálmán, Sára et al. (2015) Coordinated messenger RNA/microRNA changes in fibroblasts of patients with major depression. Biol Psychiatry 77:256-265
Kálmán, Sára; Garbett, Krassimira A; Vereczkei, Andrea et al. (2014) Metabolic stress-induced microRNA and mRNA expression profiles of human fibroblasts. Exp Cell Res 320:343-53
Shelton, Richard C; Miller, Andrew H (2010) Eating ourselves to death (and despair): the contribution of adiposity and inflammation to depression. Prog Neurobiol 91:275-99
Hahn, M K; Blackford, J U; Haman, K et al. (2008) Multivariate permutation analysis associates multiple polymorphisms with subphenotypes of major depression. Genes Brain Behav 7:487-95
Shelton, Richard C (2007) The molecular neurobiology of depression. Psychiatr Clin North Am 30:1-11
Myers, Regina L; Airey, David C; Manier, D Hal et al. (2007) Polymorphisms in the regulatory region of the human serotonin 5-HT2A receptor gene (HTR2A) influence gene expression. Biol Psychiatry 61:167-73
Akin, Demet; Manier, D Hal; Sanders-Bush, Elaine et al. (2005) Signal transduction abnormalities in melancholic depression. Int J Neuropsychopharmacol 8:5-16
Shelton, Richard C; Liang, Shan; Liang, Peng et al. (2004) Differential expression of pentraxin 3 in fibroblasts from patients with major depression. Neuropsychopharmacology 29:126-32
Akin, Demet; Manier, D Hal; Sanders-Bush, Elaine et al. (2004) Decreased serotonin 5-HT2A receptor-stimulated phosphoinositide signaling in fibroblasts from melancholic depressed patients. Neuropsychopharmacology 29:2081-7

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