This R21 exploratory application tests the hypothesis that the serotonergic activity will be adversely impacted in different brain regions of HIV-1+ cases. HIV-1 enters the central nervous system (CNS) immediately after initial infection and localizes itself with variable concentration in different brain regions, resulting in progressive neurodegeneration. It is proposed that HIV-1 induced degeneration of neurons of high monoaminergic activity, such as that of serotonin (5- hydroxytryptamine, 5-HT) may have a wide range of health implications, including depression and other neuropsychiatric disorders, neurological abnormalities, and neurocognitive impairment. Depression is one of the most common neuropsychiatric disorders in a large number of HIV-1 infected individuals, and affects their quality of life, interferes in adherence to treatment, and is a risk factor for disease progression, and mortality. The etiology of depression in HIV-1 infection is found to be complex and may involve a number of contributing factors including dysfunctions of neurobiological systems particularly, the central serotonin system. However, to date, investigations on the central serotonergic mechanisms and their relationship with depression in HIV-1 infection has remained under investigated and poorly understood. In order to investigate the central serotonergic mechanisms in HIV-1 infected individuals, the postmortem brain tissues, as well as the data related with assessment of depression during life of the corresponding individuals are required. In recent years, both of these requirements have been accomplished by the brain banks established by the NIH sponsored National NeuroAIDS Tissue Consortium (NNTC), which has made possible the availability of well characterized samples of different brain regions of HIV-1+ and HIV-1- cases, and has provided the opportunity for investigations such as those proposed in this project. It is proposed to investigate the central serotonergic activity in the postmortem tissue samples from different brain regions {raphe nuclei, hypothalamus, hippocampus, basal ganglia (caudate nucleus, putamen, globus pallidus), substantia nigra, amygdala and fronto-cortical regions (cingulate and subgenual cortical areas) as well as CSF} of a total of 40 adult men and women (HIV-1+ cases, N=25;HIV-1- cases N=15), age 25-55 years, belonging to the three ethnic groups (Caucasian, African Americans, Hispanics), who consented during life to participate in the NNTC project. It is hypothesized that the levels of 5-HT as well as its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) will be decreased in the above mentioned brain regions of HIV-1+ cases, compared to that in the same brain regions of HIV-1- cases;and that the 5-HT and 5-HIAA levels will be negatively correlated with the viral load in the same brain regions of HIV-1+ cases, as well as with depression scores assessed during life of the corresponding HIV-1+ individuals. We propose to examine the 5-HT and 5-HIAA levels in these brain regions of HIV-1+ individuals who were assessed during life, at least six months before death, for depression using Beck Depression Inventory (BDI), and investigate the relationship between the central regional 5-HTactivity and viral load in the same brain regions of HIV-1+ individuals, who were treated or not treated with HAART during life. The findings from this exploratory R-21 project will delineate the specific regional vulnerability to assault by HIV-1 with respect to 5-HT activity. Furthermore, the data will provide us with an opportunity for an RO1 application to investigate the other parameters of serotonergic mechanisms including 5-HT-receptors and 5-HT transporter/s in different brain regions of HIV-1 infected cases, and for exploring the possibility for new relevant strategies for treatment. PUBLIC HEALTH RELEVANCE: This R-21 proposal explores the impact of HIV-1 infection on the central nervous system serotonergic activity in different regions of post mortem brains of HIV/AIDS cases. It is proposed that HIV-1 induces neurodegeneration of various areas of the brain that are involved in serotonergic activity. We will determine the levels of 5-HT and its metabolite, 5-HIAA in the brain stem raphe nuclei, where the cell bodies of serotonergic neurons are located and 5-HT is synthesized, as well as in various other regions which are highly innervated with serotonergic projections, and are involved in a number of physiological and behavioral functions. The findings from this study will significantly enhance our understanding of the impact of HIV-1 induced central serotonergic deficits, that may be helpful in designing the intervention strategies that will contribute to modify the central serotonergic activity, and improve the quality of life of HIV-1 infected individuals.