Alterations of Dopamine-Dependent Behaviors and Inflammation by HIV Proteins

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DESCRIPTION (provided by applicant): Neurological complications are common in human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients, occurring in approximately a third of all HIV/AIDS patients. These complications include neuropathic pain, motor dysfunctions, cognitive impairments, and behavioral abnormalities, and are associated with a chronic inflammatory response in the central nervous system caused by the presence of specific proteins of HIV. In particular, areas of the brain high in dopaminergic neurons are prone to damage and disruption due to toxic levels of inflammatory mediators. The following experiments are designed to evaluate dopamine-mediated behaviors in an HIV-1 transgenic rat. This rat expresses 7 of the 9 genes involved in HIV. One of its uses has been proposed as a model for neurological deficits induced by exposure to HIV proteins. These experiments will examine the effects of chronic exposure to HIV proteins on behaviors mediated by dopamine and associated brain regions. Specific Aim 1 will examine motor functions in the HIV-1 transgenic rats, including grip strength, gait, and locomotor activity. Specific Aim 2 will examine a full time course and dose response curve to analgesic effects of morphine, as well as baseline pain responses to a hot plate stimulus. It is expected that these rats will show reduced motor functions and diminished analgesic responses to morphine, and preliminary data supports these hypotheses. Additionally, Specific Aim 3 will examine the neurobiological mechanisms of these behaviors by analyzing specific dopaminergic neuron-rich areas of the brain for markers of inflammation such as interleukin-1beta (IL-1¿), tumor necrosis factor-alpha (TNF-a), monocyte chemotactic protein-1 (MCP-1) and inducible nitric oxide synthase (iNOS) through the use of real-time reverse transcriptase polymerase chain reaction (RT-PCR) to measure messenger RNA (mRNA) and enzyme-linked immunosorbent assays (ELISAs) to measure protein. To fully understand the cumulative actions of HIV proteins, these rats will be examined across a period of 13 months to determine if CNS vulnerability is increased with length of exposure to HIV proteins. These experiments will evaluate the effects of chronic HIV protein exposure on dopaminergic systems in the central nervous system. The characterization of the alterations in dopamine-mediated behaviors will allow more investigators to research novel therapeutics to treat these devastating effects. In addition, identifying a neuroinflammatory mechanism in the dopaminergic systems in the central nervous system will provide a new target for drugs to treat neuropathy and motor dysfunctions often seen in HIV/AIDS patients.