Converging evidence from years of intensive research has implicated that a disorder of brain norepinephrine and/or serotonin occurs in major depression. However, the basic neurobiology of major depression has not yet been elucidated. The goal of this research is test the hypothesis that a distinct constellation of neurochemical/neuroanatomical deficits occurs in the noradrenergic system (in particular, the locus coeruleus) in major depression. Experiments are designed to address the issues of (1) the precise neurochemical and/or neuroanatomical alterations and (2) the specificity of alterations with respect to psychiatric illness. To address the first issue, concentrations of a number of proteins and substances will be measured throughout the locus coeruleus, and in a major limbic projection area (amygdala) in post-mortem brains from subjects with major depression and from psychiatrically normal control subjects. In particular, a number of noradrenergic and non-noradrenergic proteins which are sites of action of antidepressant drugs will be studied, along with proteins of which levels are modulated in the locus coeruleus by antidepressant treatment. Preliminary findings demonstrates that noradrenergic cell number is a major determinant of noradrenergic protein concentration in the locus coeruleus. Furthermore, cell loss in the locus coeruleus is associated with aging, Alzheimer's disease, and Parkinson's disease. Thus, if cell number in locus coeruleus is altered in psychiatric disease, such a change could complicate measurements of noradrenergic proteins in the locus coeruleus or lead to misinterpretation of neurochemical alterations in the locus coeruleus from major depressives. Thus, noradrenergic neuron density and number will be estimated stereologically in all subjects in parallel with neurochemical measurements. To address the issue of specificity, 4 groups of subjects will be studied: 1) no psychiatric diagnosis, age-matched control subjects dying of natural or accidental causes, 2) suicide victims with major depression, 3) non-suicide subjects with major depression, and 4) suicide victims with Axis I diagnoses other than major depression. This research will extend and clarify major findings of research in the first grant period. Elucidation of the biochemical and/or anatomical alterations of locus coeruleus neurons associated with major depression may yield important information for the development of more effective treatments for this devastating disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH046692-08
Application #
2890431
Study Section
Clinical Neuroscience and Biological Psychopathology Review Committee (CNBP)
Program Officer
Meinecke, Douglas L
Project Start
1991-09-30
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
8
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Mississippi Medical Center
Department
Psychiatry
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Chandley, Michelle J; Szebeni, Attila; Szebeni, Katalin et al. (2014) Elevated gene expression of glutamate receptors in noradrenergic neurons from the locus coeruleus in major depression. Int J Neuropsychopharmacol 17:1569-78
Szebeni, Attila; Szebeni, Katalin; DiPeri, Timothy et al. (2014) Shortened telomere length in white matter oligodendrocytes in major depression: potential role of oxidative stress. Int J Neuropsychopharmacol 17:1579-89
Chandley, Michelle J; Szebeni, Katalin; Szebeni, Attila et al. (2013) Gene expression deficits in pontine locus coeruleus astrocytes in men with major depressive disorder. J Psychiatry Neurosci 38:276-84
Ordway, Gregory A; Szebeni, Attila; Chandley, Michelle J et al. (2012) Low gene expression of bone morphogenetic protein 7 in brainstem astrocytes in major depression. Int J Neuropsychopharmacol 15:855-68
Fan, Y; Huang, J; Duffourc, M et al. (2011) Transcription factor Phox2 upregulates expression of norepinephrine transporter and dopamine ýý-hydroxylase in adult rat brains. Neuroscience 192:37-53
Mandela, Prashant; Chandley, Michelle; Xu, Yao-Yu et al. (2010) Reserpine-induced reduction in norepinephrine transporter function requires catecholamine storage vesicles. Neurochem Int 56:760-7
Ordway, Gregory A; Szebeni, Attila; Duffourc, Michelle M et al. (2009) Gene expression analyses of neurons, astrocytes, and oligodendrocytes isolated by laser capture microdissection from human brain: detrimental effects of laboratory humidity. J Neurosci Res 87:2430-8
Karolewicz, Beata; Szebeni, Katalin; Gilmore, Tempestt et al. (2009) Elevated levels of NR2A and PSD-95 in the lateral amygdala in depression. Int J Neuropsychopharmacol 12:143-53
Karolewicz, Beata; Johnson, Laurel; Szebeni, Katalin et al. (2008) Glutamate signaling proteins and tyrosine hydroxylase in the locus coeruleus of alcoholics. J Psychiatr Res 42:348-55
Xiang, Lianbin; Szebeni, Katalin; Szebeni, Attila et al. (2008) Dopamine receptor gene expression in human amygdaloid nuclei: elevated D4 receptor mRNA in major depression. Brain Res 1207:214-24

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