Role of mitochondrial dysfunction and dopamine-dependent oxidative stress in amphetamine-induced toxicity

Julie Lotharius, Karen L. O'Malley

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

To define the molecular mechanisms underlying amphetamine (AMPH) neurotoxicity, primary cultures of dopaminergic neurons were examined for drug-induced changes in dopamine (DA) distribution, oxidative stress, protein damage, and cell death. As in earlier studies, AMPH rapidly redistributed vesicular DA to the cytoplasm, where it underwent outward transport through the DA transporter. DA was concurrently oxidized to produce a threefold increase in free radicals, as measured by the redox-sensitive dye dihydroethidium. Intracellular DA depletion using the DA synthesis inhibitor α-methyl-p-tyrosine or the vesicular monoamine transport blocker reserpine prevented drug-induced free radical formation. Despite these AMPH-induced changes, neither protein oxidation nor cell death was observed until 1 and 4 days, respectively. AMPH also induced an early burst of free radicals in a CNS-derived dopaminergic cell line. However, AMPH-mediated attenuation of ATP production and mitochondrial function was not observed in these cells until 48 to 72 hours. Thus, neither metabolic dysfunction nor loss of viability was a direct consequence of AMPH neurotoxicity. In contrast, when primary cultures of dopaminergic neurons were exposed to AMPH in the presence of subtoxic doses of the mitochondrial complex I inhibitor rotenone, cell death was dramatically increased, mimicking the effects of a known parkinsonism-inducing toxin. Thus, metabolic stress may predispose dopaminergic neurons to injury by free radical-promoting insults such as AMPH.

Original languageEnglish
Pages (from-to)79-89
Number of pages11
JournalAnnals of neurology
Volume49
Issue number1
DOIs
StatePublished - 2001

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