DESCRIPTION: (Verbatim from the Applicant's Abstract) Suicide has biological and psychosocial components. We have evidence consistent with lower serotonergic activity in the prefrontal cortex (PFC) of suicide victims and in individuals with a history of a Major Depressive Episode (MDE). We found fewe serotonin transporter (SERT) sites in the ventral PFC in suicides, while patients with MDE have a widespread reduction in SERT throughout the PFC. In suicide, 5-HT1A receptors are increased in the ventral PFC, but are not significantly altered in MDE. The dorsal raphe nucleus (DRN) contains the serotonin neurons that innervate the forebrain. We found that suicide victims have more serotonergic neurons in the DRN, suggesting the reduced serotonergic activity in suicides is not due to a loss of serotonin neurons. In depressed suicides, we observe less SERT and less 5-HT1A binding in the DRN. The reduction in SERT sites is accompanied by reduced SERT mRNA in the entire DRN of suicides and fewer neurons expressing SERT mRNA. Despite more neurons, there is evidence of hypofunction (lower brainstem and CSF 5-HIAA). In the next funding period we propose to further differentiate the anatomical distribution and molecular components o abnormalities associated with suicide compared with major depression. We have four specific aims: 1) To determine levels of the rate-limiting, 5-HT biosynthetic enzyme (TPH). We will do this by immunoautoradiography and HPLC analysis in the DRN. 2) Determine whether the amount of mRNA for the SERT and 5-HT1A receptor are altered and parallel the respective protein levels. We will measure both receptor binding and mRNA in the DRN. 3) Examine the integrity of 5-HTIA and 5-HT2A receptor G-protein coupling. We will measure agonist-stimulated GTPyS binding in PFC. 4) Quantify neuronal and glial elements in the PFC. We will use stereology to measure the cell density in the ventral PFC, thus obtaining SERT terminals/5-HT1A binding per cell. We will perform these studies in matched triplets of depressed suicides (n= 15), nondepressed suicides (n=1 5) and nonpsychiatric controls (n=15). To further separate the effects of MDE from suicide, we will examine a second group of matched triplets with depressed nonsuicide (n=8), depressed suicide (n=8) and normal controls (n=8). The studies proposed will be the first comprehensive examination of serotonergic receptors, neuronal integrity and gene expression in the PFC and brainstem in suicide and MDE. 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.