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.
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