The opioid system plays a fundamental role in the pathogenesis of AIDS. Brain regions expressing a high number/density of opioid receptors, such as the striatum and hippocampus, display increased viral load and are preferentially decimated by HIV infection. The progression to AIDS dementia in HIV-positive individuals may also be markedly accelerated in opiate drug abusers. Although the virus itself propagates in microglia and astroglia, HIV-1 proteins such as gp120 and Tat, are subsequently released and cause degeneration in neighboring neurons. """"""""Opiates"""""""" (substances derived from the opium poppy, such as heroin) or analogues (e. g., OxyContin) are popular drugs of abuse. Although many aspects of HIV are caused indirectly by infected macrophages/microglial cells, direct toxic effects of the viral proteins themselves can be seen in isolated neurons. This direct neurotoxicity is exacerbated by mu opiate drugs. This proposal focuses on the interactions between mu opioids and HIV-1 proteins that result in direct synergistic neurotoxicity. Morphine synergistically increases Tat neurotoxicity via a pathway that is mediated in part by caspase-3. Our hypothesis is that opiates exacerbate neurodegenerative effects of HIV-1 by disrupting cellular homeostasis and increasing the probability of pro-apoptotic intracellular events. Disruptions in premitochondrial pathways involving PI3K, Akt, PTEN, calcium, calcineurin, and GSKSbeta will be examined for effects on both caspase- 3 dependent and independent (endonuclease-G) cell death using pharmacological, transfection (silencing/ overexpression vectors) and genetic strategies [caspase-3(-/-) and PTEN(-) mice]. Complementary in vivo/ in vitro approaches will identify the mechanisms by which mu opiates affect the survival of gp120/Tat- compromised striatal neurons.
Aim 1 will explore the mechanisms by which opiate drugs exacerbate gp120/ Tat-induced neuronal death in vitro.
Aim 2 will identify the effects of opiates on gp12Q7Tat-induced neurotoxicity in vivo using conditional Tat and gp120 expressing transgenic mice, and caspase-3 knockout and PTEN-deficient mice injected intrastriatally with Tat/gp120. Our long-term goal is to define the mechanisms by which opiate drug abuse contributes to neurodegeneration accompanying HIVE in the CNS, and to identify the underlying signaling pathways that could be targeted for therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA018633-02
Application #
7126886
Study Section
Special Emphasis Panel (ZRG1-AARR-A (05))
Program Officer
Lawrence, Diane M
Project Start
2005-09-30
Project End
2007-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
2
Fiscal Year
2006
Total Cost
$178,822
Indirect Cost
Name
University of Kentucky
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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Schier, Christina J; Marks, William D; Paris, Jason J et al. (2017) Selective Vulnerability of Striatal D2 versus D1 Dopamine Receptor-Expressing Medium Spiny Neurons in HIV-1 Tat Transgenic Male Mice. J Neurosci 37:5758-5769
Marks, William D; Paris, Jason J; Schier, Christina J et al. (2016) HIV-1 Tat causes cognitive deficits and selective loss of parvalbumin, somatostatin, and neuronal nitric oxide synthase expressing hippocampal CA1 interneuron subpopulations. J Neurovirol 22:747-762
Fitting, Sylvia; Stevens, David L; Khan, Fayez A et al. (2016) Morphine Tolerance and Physical Dependence Are Altered in Conditional HIV-1 Tat Transgenic Mice. J Pharmacol Exp Ther 356:96-105
Guedia, Joy; Brun, Paola; Bhave, Sukhada et al. (2016) HIV-1 Tat exacerbates lipopolysaccharide-induced cytokine release via TLR4 signaling in the enteric nervous system. Sci Rep 6:31203
Hahn, Yun K; Paris, Jason J; Lichtman, Aron H et al. (2016) Central HIV-1 Tat exposure elevates anxiety and fear conditioned responses of male mice concurrent with altered mu-opioid receptor-mediated G-protein activation and ?-arrestin 2 activity in the forebrain. Neurobiol Dis 92:124-36
Hahn, Yun Kyung; Podhaizer, Elizabeth M; Farris, Sean P et al. (2015) Effects of chronic HIV-1 Tat exposure in the CNS: heightened vulnerability of males versus females to changes in cell numbers, synaptic integrity, and behavior. Brain Struct Funct 220:605-23
Fitting, S; Ngwainmbi, J; Kang, M et al. (2015) Sensitization of enteric neurons to morphine by HIV-1 Tat protein. Neurogastroenterol Motil 27:468-80
El-Hage, Nazira; Rodriguez, Myosotys; Podhaizer, Elizabeth M et al. (2014) Ibudilast (AV411), and its AV1013 analog, reduce HIV-1 replication and neuronal death induced by HIV-1 and morphine. AIDS 28:1409-19
Sorrell, Mary E; Hauser, Kurt F (2014) Ligand-gated purinergic receptors regulate HIV-1 Tat and morphine related neurotoxicity in primary mouse striatal neuron-glia co-cultures. J Neuroimmune Pharmacol 9:233-44

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