Methamphetamine is a drug of abuse and in high doses causes toxicity to dopaminergic terminals in striatum as well as other neural components. The mechanism associated with this toxicity is not known although oxidative stress, dopamine, and hyperthermia have been hypothesized to play a role in the toxic outcome. Several studies have suggested that mitochondrial dysfunction may play a role in the mechanism of methamphetamine-induced neurotoxicity, but this has not been examined directly. Therefore, in this application, we propose to examine the hypothesis that mitochondrial dysfunction resulting from exposure to high doses of methamphetamine is a critical step in the resulting neurotoxicity. We will focus on the fundamental question of whether exposure to methamphetamine causes mitochondrial dysfunction by direct effects of methamphetamine, indirect effects such as increases in cytoplasmic dopamine, or a combination of both, resulting in DA terminal damage or cell death. We propose to examine this in a variety of in vitro and in vivo models taking advantage of the unique characteristics of each system. In increasingly complex systems, we will examine mitochondrial function and cell viability following acute and chronic exposure to methamphetamine in (1) isolated mitochondria and synaptosomes, (2) cell cultures, (3) cortico-striatal-mesenephalic organotypic cultures, and (4) the in vivo rat model. In the rat model, in addition to the functional analyses of mitochondria, we will also examine mitochondrial protein modifications and potential therapeutic approaches to enhance mitochondrial function and limit toxicity. We know that individuals who abuse amphetamines, even the occasional binge abuser, are at increased risk for the development of permanent damage to the CNS. This may also predispose them later in life to neurological disorders such as Parkinson's disease. The ultimate goal of this study will be to identify new targets and approaches for therapeutic intervention to prevent methamphetamine-induced neurotoxicity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA009601-07
Application #
6697040
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (02))
Program Officer
Lin, Geraline
Project Start
1996-09-01
Project End
2005-12-31
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
7
Fiscal Year
2004
Total Cost
$252,068
Indirect Cost
Name
University of Pittsburgh
Department
Neurology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Van Laar, Victor S; Mishizen, Amanda J; Cascio, Michael et al. (2009) Proteomic identification of dopamine-conjugated proteins from isolated rat brain mitochondria and SH-SY5Y cells. Neurobiol Dis 34:487-500
Dukes, April A; Van Laar, Victor S; Cascio, Michael et al. (2008) Changes in endoplasmic reticulum stress proteins and aldolase A in cells exposed to dopamine. J Neurochem 106:333-46
Van Laar, Victor S; Dukes, April A; Cascio, Michael et al. (2008) Proteomic analysis of rat brain mitochondria following exposure to dopamine quinone: implications for Parkinson disease. Neurobiol Dis 29:477-89
Dukes, April A; Korwek, Kimberly M; Hastings, Teresa G (2005) The effect of endogenous dopamine in rotenone-induced toxicity in PC12 cells. Antioxid Redox Signal 7:630-8
Perez, Ruth G; Hastings, Teresa G (2004) Could a loss of alpha-synuclein function put dopaminergic neurons at risk? J Neurochem 89:1318-24
LaVoie, Matthew J; Card, J Patrick; Hastings, Teresa G (2004) Microglial activation precedes dopamine terminal pathology in methamphetamine-induced neurotoxicity. Exp Neurol 187:47-57
Zigmond, Michael J; Hastings, Teresa G; Perez, Ruth G (2002) Increased dopamine turnover after partial loss of dopaminergic neurons: compensation or toxicity? Parkinsonism Relat Disord 8:389-93
Berman, S B; Watkins, S C; Hastings, T G (2000) Quantitative biochemical and ultrastructural comparison of mitochondrial permeability transition in isolated brain and liver mitochondria: evidence for reduced sensitivity of brain mitochondria. Exp Neurol 164:415-25
Stokes, A H; Hastings, T G; Vrana, K E (1999) Cytotoxic and genotoxic potential of dopamine. J Neurosci Res 55:659-65
LaVoie, M J; Hastings, T G (1999) Dopamine quinone formation and protein modification associated with the striatal neurotoxicity of methamphetamine: evidence against a role for extracellular dopamine. J Neurosci 19:1484-91

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