A SELECTIVE TOXICITY TOWARD CULTURED MESENCEPHALIC DOPAMINERGIC-NEURONS IS INDUCED BY THE SYNERGISTIC EFFECTS OF ENERGETIC METABOLISM IMPAIRMENT AND NMDA RECEPTOR ACTIVATION

Numerous observations strongly support the hypothesis that dopaminergi c neurons could be particularly vulnerable to an impairment of their e nergetic metabolism. In order to demonstrate the existence of such a s elective vulnerability, the toxic effects of rotenone, an inhibitor of complex I of the respiratory chain, and of glutamate, which is very l ikely involved in the neurotoxicity induced by an energetic stress, we re analyzed on cultured mouse mesencephalic neurons. Toxicity toward d opaminergic and GABAergic neurons was compared by measuring the residu al uptakes of dopamine and GABA. Exposure to 5 nM rotenone for 6 hr or to a low concentration of glutamate (100 mu M) for 1 hr did not lead to a high selective toxic effect on dopaminergic neurons. In contrast, dopaminergic neurons were three times less resistant to the sequentia l exposure to rotenone and glutamate than GABAergic neurons. A particu lar resistance of mesencephalic GABAergic neurons to the synergistic t oxic effects of rotenone and glutamate was ruled out since two other n euronal types, the striatal cholinergic and GABAergic neurons, display ed the same weak vulnerability as the mesencephalic GABAergic neurons. This selective toxic effect of glutamate on rotenone-pretreated dopam inergic neurons was blocked by either AMPA or NMDA receptor antagonist s and mimicked by combined treatment with AMPA and NMDA, or by NMDA al one when the medium was deprived of Mg2+ ions. Moreover, this NMDA-sel ective neurotoxicity was critically dependent on the presence of a phy siological extracellular sodium concentration, since the use of cholin e chloride instead of sodium chloride had a protective effect on dopam inergic neurons. Our results indicate that both the activation of NMDA receptors and the impairment of the energetic metabolism induce a sel ective toxicity toward mesencephalic dopaminergic neurons. This could therefore explain their natural degeneration in the course of Parkinso n's disease, in which mitochondrial abnormalities have been recently d escribed.