Several lines of evidence indicate that the basal ganglia are highly susceptible to infection with the human immunodeficiency virus (HIV). However, the pathogenesis of basal ganglia dysfunction is not well understood. Patients with HIV infection often abuse drugs such as methamphetamine, a drug that is well known to also cause long-term structural and functional changes to the basal ganglia. There is now mounting evidence that """"""""virotoxins"""""""" (viral products released from infected cells) and methamphetamine share a common mechanism, which leads to neuronal damage. Two such products are the HIV proteins gp120 and Tat. In this proposal, we will examine the degree of synergy between these virotoxins and methamphetamine by determining the severity of damage they cause to the dopaminergic system in vivo and to human cortical neurons in vitro. To identify common mechanisms that lead to neuronal dysfunction and ultimately, to cell death, we will also examine two pathophysiological processes that contribute independently to virotoxin and MA toxicity, namely reactive oxygen species and the cytokine TNF-alpha. In studying these two processes, we will 2) measure production of compounds of interest (e.g. reactive oxygen species and TNF-alpha) and determine the efficacy of a variety of inhibitors on neurotoxicity. To accomplish these goals, we will assess the effects of intrastriatal injections of virotoxins in animals treated with methamphetamine and in vitro in human cortical neurons where cell types can be manipulated.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA013144-03
Application #
6626834
Study Section
Special Emphasis Panel (ZRG1-AARR-5 (01))
Program Officer
Sharp, Charles
Project Start
2001-02-15
Project End
2005-12-31
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
3
Fiscal Year
2003
Total Cost
$289,600
Indirect Cost
Name
University of Kentucky
Department
Neurology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Theodore, Shaji; Cass, Wayne A; Nath, Avindra et al. (2007) Progress in understanding basal ganglia dysfunction as a common target for methamphetamine abuse and HIV-1 neurodegeneration. Curr HIV Res 5:301-13
Hauser, Kurt F; El-Hage, Nazira; Stiene-Martin, Anne et al. (2007) HIV-1 neuropathogenesis: glial mechanisms revealed through substance abuse. J Neurochem 100:567-86
Theodore, Shaji; Cass, Wayne A; Maragos, William F (2006) Involvement of cytokines in human immunodeficiency virus-1 protein Tat and methamphetamine interactions in the striatum. Exp Neurol 199:490-8
Theodore, S; Cass, W A; Maragos, W F (2006) Methamphetamine and human immunodeficiency virus protein Tat synergize to destroy dopaminergic terminals in the rat striatum. Neuroscience 137:925-35
Theodore, Shaji; Stolberg, Stephanie; Cass, Wayne A et al. (2006) Human immunodeficiency virus-1 protein tat and methamphetamine interactions. Ann N Y Acad Sci 1074:178-90
Theodore, Shaji; Cass, Wayne A; Nath, Avindra et al. (2006) Inhibition of tumor necrosis factor-alpha signaling prevents human immunodeficiency virus-1 protein Tat and methamphetamine interaction. Neurobiol Dis 23:663-8
Korde, Amit S; Sullivan, Patrick G; Maragos, William F (2005) The uncoupling agent 2,4-dinitrophenol improves mitochondrial homeostasis following striatal quinolinic acid injections. J Neurotrauma 22:1142-9
Cass, Wayne A; Harned, Michael E; Peters, Laura E et al. (2003) HIV-1 protein Tat potentiation of methamphetamine-induced decreases in evoked overflow of dopamine in the striatum of the rat. Brain Res 984:133-42
Maragos, William F; Young, Kristie L; Turchan, Jadwiga T et al. (2002) Human immunodeficiency virus-1 Tat protein and methamphetamine interact synergistically to impair striatal dopaminergic function. J Neurochem 83:955-63