NMDA receptors modulate dopamine loss due to energy impairment in the substantia nigra but not striatum

Defects in energy metabolism have been detected in patients with Parkinson' s disease and have been proposed as a contributing factor in the disease. P revious in vitro studies showed that NMDA receptors contribute to the loss of dopamine neurons caused by the metabolic inhibitor malonate. In vivo it is not known whether this interaction occurs through a postsynaptic action on the cell body in the substantia nigra or through a presynaptic action at the dopamine terminal in the striatum. So we could discern the anatomical level of NMDA receptor involvement, rats were infused with malonate, either into the left striatum or into the left substantia nigra. NMDA receptors w ere locally blocked by an intranigral or intrastriatal coinfusion of malona te plus MK-801 followed by a second infusion of MK-801 3 h later. Animals w ere examined at 1 week for striatal and nigral dopamine and GABA levels. In tranigral infusion of malonate (0.5 mu mol) produced an approximate 50% los s of both nigral dopamine and GABA. MK-801 (0.1 mu mol) provided significan t protection against both nigral dopamine and GABA loss and against anterog rade damage to dopamine terminals in the striatum. Intrastriatal administra tion of malonate (2 mu mol) produced a 68 and 35% loss of striatal dopamine and GABA, respectively. In contrast to intranigral administration, intrast riatal blockade of NMDA receptors did not protect against striatal dopamine loss, although GABA loss was significantly attenuated. Core body temperatu re monitored several hours throughout the experiment was unchanged. Consist ent with a lack of effect of NMDA antagonists on malonate-induced toxicity to dopamine neurons in striatum, intrastriatal infusion of NMDA had a prono unced effect on long-term GABA toxicity with little effect of dopamine loss . These findings are consistent with a postsynaptic action of NMDA receptor s on mediating toxicity to dopamine neurons during impaired energy metaboli sm. (C) 2000 Academic Press.