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 inhibito r of succinate dehydrogenase (SDH), 3-nitropropionic acid (3-NPA), for 24 h on day 12 in vitro, produced a dose-dependent loss of high-affin ity dopamine uptake when measured 48 h following 3-NPA removal. ATP co ncentrations in the cultures were reduced by 57% after 3 h of treatmen t with the highest concentration of 3-NPA tested (500 mu M) To determi ne whether glutamate receptors mediated the dopamine toxicity by 3-NPA , cultures were examined for their sensitivity to excitatory amino aci d-induced toxicity. Mesencephalic cultures exposed to either 100 mu 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 mu M) or 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 15 mu 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 dopam ine 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 d opamine neurons can trigger a secondary excitotoxicity that is mediate d by NMDA receptors.