Suicide has a biological and psychosocial basis. We have evidence of altered serotonergic and noradrenergic activity consistent with decreased serotonergic and increased noradrenergic activity in the prefrontal cortex of suicide victims. W found: (1) increases in 5- HT(1A) receptor binding and reduced serotonin transporter binding in ventrolateral area prefrontal cortex; (2) increases in 5-HT(2A) binding mostly in ventromedial prefrontal cortex; (3) altered density of serotonin neurons in brainstem; (4) no alteration in 5-HT and 5- hydroxyindoleacetic acid (5-HIAA) levels, transporter binding or 5- HT(1D), 5-HT(1A) and 5-HT(2A) binding in dorsolateral prefrontal cortex; (5) high affinity beta1-adrenergic and alpha2-adrenergic binding are decreased whereas alpha1-adrenergic binding is increased in prefrontal cortex; (6) norepinephrine (NE) levels are higher in Brodmann areas 9 and 38; and (7) suicides have fewer noradrenergic neurons but increased levels of tyrosine hydroxylase. Overall, serotonergic changes are most pronounced in ventral prefrontal cortex. Noradrenergic cortical changes are more diffuse. We now propose to identify the locus of alteration in the serotonergic system in suicide at an anatomical level and at a cellular or biochemical level. Our current proposal aims to determine: a) whether alterations in the serotonergic functions are due to primary changes in serotonin neurons at the level of the brainstem nuclei or in the prefrontal cortical target areas where serotonin receptor changes have been found, ie. ventral PFC. We will assess dorsal raphe nuclei serotonin neurons. and cortical neurons in a key target region (Brodmann areas 45 & 46), utilizing adjacent slide-mounted sections to combine receptor autoradiography,in situ hybridization histochemistry for mRNA for the same serotonin receptors and serotonin-related proteins, and quantitative morphometry of serotonin neurons and cortical neurons; b) we will distinguish specific neurochemical correlates of suicide versus a depressive illness by comparing suicides with a recent Major Depressive Episode (MDE) (n=20) to suicides with no history of MDE (n=20) to nonpsychiatric, nonsuicides (n=20). To further determine the molecular basis for serotenergic dysfunction we will assay membrane binding kinetics and serotonin receptor coupled G protein function. We propose to establish whether there is a localized, biochemically specific alteration in the serotonergic system underlying suicidal behavior, independent of Major Depression. Such a conclusion would have profound consequences for conceptualizing the basis of suicidal behavior as well as the development of diagnostic imaging tests and effective, specific pharmacotherapy of suicide, the cause of death of over 30,000 people per year in the United States.
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