Disturbances in serotonin (5HT) metabolism in brain have been implicated in the pathogenesis of affective disorders and suicide. The objective of this novel application is to examine the hypothesis that suicide victims with a history of unipolar or bipolar depression (as opposed to normal controls or suicides without a history of depression) demonstrate a dysfunction of the 5HT system in the forebrain and brainstem raphe nuclei. The premise of the proposed studies examining binding to 5HT receptor subtypes in forebrain is that the observed decrement in midbrain content of 5HT in suicides may be relate to 5HT receptor supersensitivity in the forebrain in suicide victims with a history of depression. Decreased numbers of 5HT-1A autoreceptors or diminished amounts of tryptophan hydroxylase in the midbrain raphe may underlie the decrease in the content of 5HT in the brainstem of suicide victims and be responsible for clinical depression. The proposed postmortem studies are unique in correlating several markers for 5HT in the same blocks of tissue with premortem psychiatric disorders in suicide victims.
Specific aims of this research include: << 1) To collect brain tissue from suicide victims and psychiatrically normal controls dying by natural causes, accidents or homicides, and compile toxicological data and perform psychological autopsies on all cases. Criteria for exclusion from serotonin receptor studies would include: neurological history or neuropathology, or recent antidepressant therapy. Alcohol or psychoactive substance use disorder in suicide will also be controlled for >>; 2) To examine the hypothesis that 5HT-1A and 5HT-2 receptor binding is increased in the frontal cortex (areas 8 & 9, 10) and hippocampus of suicide victims with a history of depression as compared to << suicide without a history of depression and >> controls (depression is defined as unipolar or bipolar depression); 3) To examine the hypothesis that binding to the serotonin uptake recognition site is decreased in frontal cortex, hippocampus, dorsal an median raphe nuclei in suicide victims with a history of depression as compared to << suicides without a history of depression and >> controls; 4) To examine the hypothesis that 5HT-1A receptor binding in the dorsal and median raphe nuclei is increased in suicide victims with a history of depression as compared to << suicides without a history of depression and >> controls; and 5) To examine the hypothesis that the content of 5HT and 5- hydroxyindoleacetic acid is decreased, and <> is increased in the dorsal raphe nucleus, in suicide victims with a history of depression compared to << suicides without a history of depression and >> controls. The proposed studies will provide a critical and unique test of the hypothesis that alterations in 5HT receptor number are linked to depression in suicide. Measurement of 5HT receptor binding in brain regions of depressed suicide victims may prove to be an important indirect indicator of central 5HT neuron function in mood disorder and suicide. Examining multiple features of 5HT neurons at the cell bodies of origin and in projection areas is a unique approach to examining the role of 5HT in depression and suicide. These studies should provide preliminary steps toward the eventual goal of imaging monoamine receptors in vivo in patients suffering from depression and suicidal ideation.

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National Institute of Mental Health (NIMH)
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Biological Psychopathology Review Committee (BPP)
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Case Western Reserve University
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