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. Previous in vitro studies showed that NMDA receptors contribute to the loss of dopamine neurons caused by the metabolic inhibitor malonate. In viv...

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Bibliographic Details
Published in:Experimental neurology 2000-02, Vol.161 (2), p.638-646
Main Authors: Zeevalk, Gail D., Manzino, Lawrence, Sonsalla, Patricia K.
Format: Article
Language:English
Subjects:
Animals
basal ganglia
Body Temperature
Corpus Striatum - drug effects
Corpus Striatum - physiology
Dizocilpine Maleate - administration & dosage
Dizocilpine Maleate - pharmacology
Dopamine - metabolism
Excitatory Amino Acid Antagonists - administration & dosage
Excitatory Amino Acid Antagonists - pharmacology
Functional Laterality
gamma-Aminobutyric Acid - metabolism
glutamate receptors
Infusions, Parenteral
Male
malonate
Malonates - administration & dosage
Malonates - pharmacology
midbrain
mitochondria
Neurons - cytology
Neurons - drug effects
Neurons - physiology
Parkinson's disease
Rats
Rats, Sprague-Dawley
Receptors, N-Methyl-D-Aspartate - physiology
Substantia Nigra - drug effects
Substantia Nigra - physiology
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Summary:Defects in energy metabolism have been detected in patients with Parkinson's disease and have been proposed as a contributing factor in the disease. Previous 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 were locally blocked by an intranigral or intrastriatal coinfusion of malonate plus MK-801 followed by a second infusion of MK-801 3 h later. Animals were examined at 1 week for striatal and nigral dopamine and GABA levels. Intranigral infusion of malonate (0.5 μmol) produced an approximate 50% loss of both nigral dopamine and GABA. MK-801 (0.1 μmol) provided significant protection against both nigral dopamine and GABA loss and against anterograde damage to dopamine terminals in the striatum. Intrastriatal administration of malonate (2 μmol) produced a 68 and 35% loss of striatal dopamine and GABA, respectively. In contrast to intranigral administration, intrastriatal blockade of NMDA receptors did not protect against striatal dopamine loss, although GABA loss was significantly attenuated. Core body temperature monitored several hours throughout the experiment was unchanged. Consistent with a lack of effect of NMDA antagonists on malonate-induced toxicity to dopamine neurons in striatum, intrastriatal infusion of NMDA had a pronounced effect on long-term GABA toxicity with little effect of dopamine loss. These findings are consistent with a postsynaptic action of NMDA receptors on mediating toxicity to dopamine neurons during impaired energy metabolism.
ISSN:0014-4886
1090-2430
DOI:10.1006/exnr.1999.7283