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NMDA Receptor Involvement in Toxicity to Dopamine Neurons In Vitro Caused by the Succinate Dehydrogenase Inhibitor 3‐Nitropropionic Acid
Author(s) -
Zeevalk Gail D.,
DerrYellin Ethel,
Nicklas William J.
Publication year - 1995
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1995.64010455.x
Subject(s) - cnqx , kainate receptor , nmda receptor , excitotoxicity , dopamine , glutamate receptor , chemistry , kainic acid , dizocilpine , pharmacology , medicine , ampa receptor , receptor , endocrinology , biology , biochemistry
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 µ M ). 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 µ M 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 µ M ) or 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX; 15 µ M ), 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.