Repeated administration of methamphetamine (METH) results in selective toxicity toward dopamine (DA) and serotonin terminals in the striatum. This toxicity is dependent on the presence of DA in this same brain region. Oxidative stress has been implicated in METH-induced toxicity, as well. Therefore, DA oxidation has been proposed as a link between these observations. Recently, nitric oxide has also been implicated in METH- induced toxicity. There are three possible sources of nitric oxide, and this proposal attempts to address how nitric oxide syntheses is activated by METH, how this may relate to toxicity, and eventually what cells are responsible. DA and NO or peroxynitrite may interact and lead to increased DA oxidation and DA-induced toxicity. This possibility is best addressed in vitro, and various experiments will investigate possible DA- nitric oxide interactions. The applicant's advisor has established a model of DA-induced toxicity that will be further investigated in this proposal, as well. Intratriatal administration of exogenous DA has many parallels to METH-induced toxicity, such as direct observation of DA oxidation and protection by antioxidants. METH-induced toxicity seems to involve nitric oxide, is attenuated by NMDA receptor antagonists, and results in increases in extracellular glutamate. Experiments will reveal whether DA-induced toxicity continues to parallel METH-induced striatal toxicity in these ways

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31DA005811-03
Application #
2897761
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Lin, Geraline
Project Start
1999-08-10
Project End
Budget Start
1999-08-10
Budget End
2000-08-09
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Neurosciences
Type
Schools of Arts and Sciences
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213