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
