Converging evidence from years of intensive research has implicated that a disorder of central norepinephrine (NE) exists in depression. However, the basic neurobiology of depression has not yet been elucidated. The goal of this research proposal is to study the noradrenergic system in brain tissue from victims of suicide retrospectively identified as depressed. The components of the noradrenergic system studied here include that which responds to changes in noradrenergic neuronal activity (tyrosine hydroxylase mRNA), receptors which modulate NE release (alpha-2 adrenoceptors), receptors which are regulated by the concentrations of brain NE (alpha-2 adrenoceptors, beta adrenoceptors), neuropeptides which are colocalized with NE which modulate NE release (neuropeptide Y, galanin), and NE itself. The proposed studies are unique in that they will investigate noradrenergic chemistry in discrete brain regions, particularly the limbic system and the locus coeruleus, the principal source of NE in the brain. Furthermore, extensive psychological histories of the suicide completers will be obtained and used to determine if diagnoses of unipolar depression or bipolar affective disorder are correlated with alterations in noradrenergic chemistry. It is postulated here that an aberrant brain noradrenergic system in depression would manifest altered levels of mRNA encoding tyrosine hydroxylase and/or noradrenergic receptors in noradrenergic nuclei of the brainstem (e.g. locus coeruleus), and in specific terminal fields of these nuclei. Utilization of the techniques of quantitative in situ hybridization and receptor autoradiography to measure mRNAs and receptors requires small amounts of tissue. Thus, multiple components of the noradrenergic system can be measured at the discrete neuroanatomical and cellular level in the same individual; and multivariate statistics can be used analyze data for systematic changes across individuals as well as across groups.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH046692-01A2
Application #
3386533
Study Section
Neurosciences Research Review Committee (BPN)
Project Start
1991-09-30
Project End
1995-08-31
Budget Start
1991-09-30
Budget End
1992-08-31
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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

Showing the most recent 10 out of 11 publications