This project will elucidate the neurochemical mechanism and clinical implications of abnormal dopaminergic (DAergic) synaptic transmission in people with HIV/AIDS. The concept follows from original preliminary data that have established that DAergic synapses are biochemically abnormal in people with HIV-associated dementia and HIV encephalitis (HIVE). Abnormal DAergic transmission is related to neurocognitive impairment, psychosis, depression, addictive behavior and motor slowing. All of those problems occur with high prevalence in people with HIV/AIDS. To determine the clinical significance of abnormal DAergic transmission in HIV/AIDS, we will perform a circuit-level biochemical analysis of autopsy brain specimens. The baseline aim will determine whether HIV encephalitis (HIVE) is required to produce abnormal DAergic synapses and, whether or not the anomaly is related to virological and immunological changes in blood and CSF. A second aim will address important clinical implications of abnormal DAergic synapses, including involvement in frontal lobe dysfunction, drug abuse, psychosis, and mood disorders. In those studies, specific DAergic circuits that drive abnormal behavior will be isolated and studied. The final aim addresses the pathophysiology of abnormal DAergic systems, to include the neuropathological, neurovirological, neurochemical and neuroimmunological aspects. We also will evaluate the influence of comorbid conditions that can produce neurological changes, including hepatitis C virus infection and antiretroviral therapies. The analysis will be done with brain specimens from the National NeuroAIDS Tissue Consortium (NNTC). The NNTC database contains detailed information regarding neuropsychological changes, substance abuse, comorbid factors, clinical virology and immunology of the decedents. Our results would provide the neuroAIDS field with bedrock neurochemical and neuropathological data on abnormal DAergic systems, and address correlations with many clinical problems and comorbidities of the people with HIV/AIDS. The neurobiological "blueprint" that we will pursue will help formulate strategies for clinical management of DAergic dysfunction, including its potential influence on frontal lobe dysfunction and neuropsychiatric disorders. The project breaks ground neuroscientifically, as no autopsy study has advanced to a "task specific" behavioral correlation with circuit level anomalies of a specific neurotransmitter system.