Role for dopamine in malonate-induced damage in vivo in striatum and in vitro in mesencephalic cultures

Defects in mitochondrial energy metabolism have been implicated in the path ology of several neuro-degenerative disorders. In addition, the reactive me tabolites generated from the metabolism and oxidation of the neurotransmitt er dopamine (DA) are thought to contribute to the damage to neurons of the basal ganglia. We have previously demonstrated that infusions of the metabo lic inhibitor malonate into the striata of mice or rats produce degeneratio n of DA nerve terminals. In the present studies, we demonstrate that an int rastriatal infusion of malonate induces a substantial increase in DA efflux in awake, behaving mice as measured by in vivo microdialysis. Furthermore, pretreatment of mice with tetrabenazine (TBZ) or the TBZ analogue Ro 4-128 4 (Ro-4), compounds that reversibly inhibit the vesicular storage of DA, at tenuates the malonate-induced DA efflux as well as the damage to DA nerve t erminals. Consistent with these findings, the damage to both DA and GABA ne urons in mesencephalic cultures by malonate exposure was attenuated by pret reatment with TBZ or Ro-4. Treatment with these compounds did not affect th e formation of free radicals or the inhibition of oxidative phosphorylation resulting from malonate exposure alone. Our data suggest that DA plays an important role in the neurotoxicity produced by malonate. These findings pr ovide direct evidence that inhibition of succinate dehydrogenase causes an increase in extracellular DA levels and indicate that bioenergetic defects may contribute to the pathogenesis of chronic neurodegenerative diseases th rough a mechanism involving DA.