ALTERATIONS OF DOPAMINE-DEPENDENT BEHAVIORS AND INFLAMMATION BY HIV PROTEINS
Alison F Wagner
University Of North Carolina Chapel Hill, Office Of Sponsored Research, Chapel Hill, Nc 27599
Grant 5F31DA026319-02 from National Institute On Drug Abuse
Abstract: 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
Keywords: 3, 4-Dihydroxyphenethylamine; 4-(2-Aminoethyl)-1, 2-benzenediol; AIDS Virus; Absence of pain sensation; Absence of sensibility to pain; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Address; Age; Analgesic Agents; Analgesic Drugs; Analgesic Preparation; Analgesics; Animal Model; Animal Models and Related Studies; Anodynes; Antinociceptive Agents; Antinociceptive Drugs; Area; Basal Ganglia; Basal Nuclei; Behavior; Behavioral; Blotting, Western; Brain; Brain region; Cachectin; Cachectin-Tumor Necrosis Factor; Cells; Central Nervous System; Central gray substance of midbrain; Chronic; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive function abnormal; Common Rat Strains; Contin, MS; Control Animal; Corpus Striatum; Corpus striatum structure; DA Neuron; Data; Disease; Disorder; Disturbance in cognition; Dopamine; Dopamine neuron; Dose; Drug Delivery; Drug Delivery Systems; Drug Targeting; Drug Targetings; Drugs; Dysfunction; ELISA; Encephalon; Encephalons; Enzyme-Linked Immunosorbent Assay; Experimental Models; Experimental Models, Other; Exposure to; Feels no pain; Functional disorder; Gait; Genes; Glia; Glial Cells; Grips; HIV; HIV-1; HIV-I; HIV1; HTLV-III; Hepatocyte Nitric Oxide Synthase; Human; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human immunodeficiency virus 1; Human, General; Hydroxytyramine; IL-1 beta; IL-1-b; IL1-Beta; IL1B Protein; IL1F2; INFLM; INOS; Immune; Immune Cell Activation; Immunodeficiency Disorder; Immunodeficiency Syndrome; Immunodeficiency Virus Type 1, Human; Immunologic Deficiency Syndromes; Immunological Deficiency Syndromes; Impaired cognition; In Vitro; Inducible Nitric Oxide Synthase; Inflammation; Inflammation Mediators; Inflammatory Response; Infumorph; Interleukin 1, Beta Proprotein; Interleukin 1beta; Interleukin-1 beta; Investigators; Kadian; Knowledge; Kolliker`s reticulum; LAV-HTLV-III; Length; Link; Locomotor Activity; Lymphadenopathy-Associated Virus; MSir; Macrophage Nitric Oxide Synthase; Mammals, Rats; Man (Taxonomy); Man, Modern; Measurement; Measures; Mediating; Mediator; Mediator of Activation; Mediator of activation protein; Medication; Mesencephalic Central Gray; Messenger RNA; Midbrain Central Gray; Modeling; Models, Experimental; Models, Neurological; Monocyte Chemoattractant Protein-1; Monocyte Chemotactic Protein-1; Monocyte Chemotactic and Activating Factor; Monocyte Chemotactic and Activating Protein; Monocyte Secretory Protein JE; Morphia; Morphinan-3, 6-diol, 7, 8-didehydro-4, 5-epoxy-17-methyl- (5alpha, 6alpha)-; Morphine; Mortality; Mortality Vital Statistics; Motor; Motor Activity; NOS Type II; NOS2; NOS2A; NOS2A protein, human; Nature; Nerve Cells; Nerve Unit; Nervous System, Brain; Nervous System, CNS; Neural Cell; Neuraxis; Neurocyte; Neuroglia; Neuroglial Cells; Neurologic; Neurologic Models; Neurological; Neurological Models; Neurons; Neuropathy; Nitric Oxide Synthase 2A; No sensitivity to pain; Non-neuronal cell; Nucleus Accumbens; Oramorph; Oramorph SR; Pain; Painful; Pathway interactions; Patients; Periaqueductal Gray; Pharmaceutic Preparations; Pharmaceutical Preparations; Physiopathology; Preinterleukin 1 Beta; Process; Production; Proteins; QOL; Quality of life; RNA, Messenger; RT-PCR; RTPCR; Rat; Rattus; Research; Research Personnel; Researchers; Reverse Transcriptase Polymerase Chain Reaction; Roxanol; Simulate; Small Inducible Cytokine A2; Statex SR; Stimulus; Striate Body; Striatum; Substantia Nigra; Substantia nigra structure; System; System, LOINC Axis 4; TNF-alpha; Testing; Time; Transgenic Organisms; Tumor Necrosis Factor; Tumor Necrosis Factor-alpha; Viral; Viral Gene Products; Viral Gene Proteins; Viral Proteins; Virus-HIV; Western Blotting; Western Blottings; Western Immunoblotting; analgesia; annulus of the aqueduct; brain tissue; cognitive dysfunction; cognitive loss; cognitively impaired; design; designing; disease/disorder; dopaminergic neuron; drug/agent; experiment; experimental research; experimental study; gene product; grasp; human NOS2A protein; human T cell leukemia virus III; human T lymphotropic virus III; hypoimmunity; iNOS enzyme; immune deficiency disorder; immunodeficiency; in vivo; inflammatory marker; mRNA; midbrain central gray substance; model organism; nerve cement; neurobiological mechanism; neuronal; neuropathic; neuropathic pain; neurotoxic; new therapeutics; next generation therapeutics; nitric oxide synthase, Type II; novel therapeutics; painful neuropathy; pathophysiology; pathway; patient population; periaqueductal gray matter; protein blotting; research study; response; reverse transcriptase PCR; striatal; transgenic; virus protein
Project start date: 2009-02-16
Project end date: 2011-02-15
Budget start date: 16-FEB-2010
Budget end date: 15-FEB-2011
5F31DA026319-02 (2010): $30044
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Alison F Wagner
Alterations Of Dopamine-Dependent Behaviors And Inflammation By HIV Proteins
Alison F Wagner
Psychologyuniversity Of North Carolina Chapel Hill
Grant 1F31DA026319-01A1 from National Institute On Drug Abuse IRG: ZRG1
Abstract: 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-1a), 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
Project start date: 2009-02-16
Project end date: 2011-02-15