Mitochondrial stress-induced dopamine efflux and neuronal damage by malonate involves the dopamine transporter.
Endogenous striatal dopamine (DA) overflow has been associated with neuropathological conditions resulting from ischemia, psychostimulants, and metabolic inhibition. Malonate, a reversible inhibitor of succinate dehydrogenase, models the effects of energy impairment in neurodegenerative disorders. We have previously reported that the striatal DA efflux and damage to DA nerve terminals resulting from intrastriatal malonate infusions is prevented by prior DA depletion, suggesting that DA plays a role in the neuronal damage. We presently report that the malonate-induced DA efflux is partially mediated by reverse transport of DA from the cytosol to the extracellular space via the DA transporter (DAT). Pharmacological blockade of the DAT with a series of structurally different inhibitors [cocaine, mazindol, 1-(2-(bis(4-fluophenyl methoxy) ethyl)-4-(3-(4-fluorophenyl)-propyl)piperazine) dimethane sulfonate (GBR 13098) and methyl(-)-3beta-(p-fluorophenyl)-1alphaH,5alphaH-tropane-2beta-carboxylate1,5-naphthalene (Win 35,428)] attenuated malonate-induced DA overflow in vivo and protected mice against subsequent damage to DA nerve terminals. Consistent with these findings, the DAT inhibitors prevented malonate-induced damage to DA neurons in mesencephalic cultures and also protected against the loss of GABA neurons in this system. The DAT inhibitors did not modify malonate-induced formation of reactive oxygen species or lactate production, indicating that the DAT inhibitors neither exert antioxidant effects nor interfere with the actions of malonate. Taken together, these findings provide direct evidence that mitochondrial impairment and metabolic stress cause striatal DA efflux via the DAT and suggest that disruptions in DA homeostasis resulting from energy impairment may contribute to the pathogenesis of neurodegenerative diseases.
Moy
Lily Y
LY
Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Wang
Sheng-Ping
SP
Sonsalla
Patricia K
PK
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000502:physiology*; D005609:Free Radicals; D019344:Lactic Acid / Q000096:biosynthesis; D008297:Male; D008314:Malonates / Q000633:toxicity*; D008636:Mesencephalon / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D050483:Dopamine Plasma Membrane Transport Proteins; D005609:Free Radicals; D008314:Malonates; D019344:Lactic Acid; D005680:gamma-Aminobutyric Acid; C030290:malonic acid; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine