NMDA receptor involvement in toxicity to dopamine neurons in vitro caused by the succinate dehydrogenase inhibitor 3-nitropropionic acid.
Exposure of mesencephalic dopamine neurons to an irreversible inhibitor of succinate dehydrogenase (SDH), 3-nitropropionic acid (3-NPA), for 24 h on day 12 in vitro, produced a dose-dependent loss of high-affinity dopamine uptake when measured 48 h following 3-NPA removal. ATP concentrations in the cultures were reduced by 57% after 3 h of treatment with the highest concentration of 3-NPA tested (500 microM). To determine whether glutamate receptors mediated the dopamine toxicity by 3-NPA, cultures were examined for their sensitivity to excitatory amino acid-induced toxicity. Mesencephalic cultures exposed to either 100 microM NMDA or kainate, on day 12 for 24 h, showed complete loss of dopamine uptake following 48 h of recovery. The NMDA and non-NMDA antagonists, MK-801 (1 microM) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 15 microM), completely prevented the effects of NMDA or kainate, respectively, when present at the time of toxin exposure. In cultures treated with 3-NPA, MK-801, but not CNQX, significantly attenuated the loss of dopamine uptake. Direct measurement of the effect of 3-NPA on SDH activity showed that 3-NPA dose-dependently inhibited SDH in vitro in a manner commensurate with the loss of dopamine uptake by 3-NPA. MK-801 had no effect on basal SDH activity or on 3-NPA inhibition of SDH. These data are consistent with the interpretation that metabolic inhibition in dopamine neurons can trigger a secondary excitotoxicity that is mediated by NMDA receptors.
Zeevalk
G D
GD
Department of Neurology, University of Medicine and Dentistry of NJ-Robert Wood Johnson Medical School, Piscataway 08854.
Derr-Yellin
E
E
Nicklas
W J
WJ
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000032:analysis / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000633:toxicity*; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000032:analysis / Q000378:metabolism; D008636:Mesencephalon / Q000166:cytology; D016202:N-Methylaspartate / Q000378:metabolism / Q000494:pharmacology; D009474:Neurons / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D009574:Nitro Compounds; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors*
D000959:Antihypertensive Agents; D009574:Nitro Compounds; D011422:Propionates; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000255:Adenosine Triphosphate; D013385:Succinate Dehydrogenase; C015392:3-nitropropionic acid; D004298:Dopamine