Alterations in serotonin neurotransmission in brain have been implicated in the pathophysiology of major depression and suicide. In addition, other support for a role of serotonin in major depression comes from animal studies in which biochemical and electrophysiological markers of serotonergic function are enhanced after chronic administration of antidepressant treatments. The objective of this application is to examine the hypothesis that suicide victims with major depression demonstrate a dysfunction of the serotonin system in the DR as compared to normal controls. These studies will compare suicide victims with major depression to: a) control subjects with no psychiatric illness, b) subjects with major depression not dying by suicide, and c) suicide victims with depressive symptomatology with an Axis I diagnosis other than major depression. These studies are designed to control for the type of psychiatric disorder and exclude psychoactive substance related disorders so the effects being analyzed will include the presence or absence of suicide and the presence or absence of major depression. Hypotheses to be tested include: 1) alterations in the serotonergic system in suicide victims will only be detected in a carefully characterized and homogeneous population of subjects with current major depression as compared to control subjects without psychiatric illness, 2) the amount of tryptophan hydroxylase in the DR will be increased in suicide victims with major depression, and 3) serotonin-1A receptors will be increased and serotonin transporters will be decreased in the DR of suicide victims with a current diagnosis of major depression as compared to normal control subjects. Since these serotonergic proteins are differentially expressed within constituent subnuclei of the DR and along the longitudinal axis of the midbrain, the DR will be sampled at several intervals along its rostral-caudal extent. Serotonin- synthesizing cell bodies within the DR will be expressed in relation to serotonergic markers within the DR can be highly affected by the location at which the DR is sampled. Evaluating multiple features of serotonin neurons at the cell bodies of origin in the brainstem is a unique approach to examining the role of serotonin in depression and suicide. These studies should provide preliminary steps toward the eventual goal of imaging monoamine neurons in vivo in patients suffering from depression and suicidal ideation. This application is part of an IRPG dedicated to examining the neurochemical and neuroanatomical organization of the cell bodies of origin and cortical projection areas of monoamine neurotransmitters in suicide and major depression.
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