Our research has led us to postulate that major depression is associated, at least in part, with noradrenergic overdrive and a deficiency of synaptic norepinephrine. This postulate is based on the fact that biochemical alterations identified by us in the postmortem locus coeruleus (LC; brain norepinephrine neurons) of major depressive subjects can be produced experimentally in rats by treatments (e.g chronic stress) that elevate noradrenergic activity and deplete central norepinephrine. Also, repeated treatment of rats with antidepressant drugs reduces LC activity and downregulates specific proteins that we have found elevated in the LC of major depressive subjects. Together, these findings suggest that abnormalities in the LC are strongly associated with major depression. The central hypothesis of this proposal is that the noradrenergic pathobiology of depression is associated with elevated excitatory and reduced inhibitory inputs to the LC. A critical component of neuronal circuitry driving emotion-laden activation of the LC is corticotropin releasing factor (CRF) input from the amygdala. This circuit and other major """"""""stress-sensitive"""""""" excitatory and inhibitory inputs to the LC, including substance P, glutamate, serotonin, and GABA, will be studied in the LC in postmortem brains from psychiatrically characterized subjects. Preliminary evidence of elevations of CRF and substance P input to the human LC in major depression is provided. Molecular pathways responsible for certain activation-induced biochemical changes in the LC include receptor-second messenger systems linked to gene expression through trans-activating factors. Potential disruption of these pathways in depression will be studied, emphasizing factors regulating long-term changes in LC gene expression. The overall goals of this application are to study neurotransmitter inputs that likely contribute to noradrenergic overdrive in major depression, and to investigate the molecular underpinnings of noradrenergic pathobiology. To achieve these goals, postmortem brain tissues from major depressive subjects (suicide and non-suicide), suicide victims lacking major depression, and carefully matched control subjects lacking major psychiatric disorders will be utilized. Diagnoses are made via a rigorous psychiatric/neurologic autopsy program under the direction of Dr. Craig Stockmeier.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BDCN-6 (01))
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Meinecke, Douglas L
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East Tennessee State University
Schools of Medicine
Johnson City
United States
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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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