INTRASTRIATAL INJECTIONS OF THE SUCCINATE-DEHYDROGENASE INHIBITOR, MALONATE, CAUSE A RISE IN EXTRACELLULAR AMINO-ACIDS THAT IS BLOCKED BY MK-801

The effects of intrastriatal,injections of a reversible inhibitor of s uccinate dehydrogenase, malonate, on the extracellular concentrations of amino acid neurotransmitters were examined using a microdialysis pr obe that was positioned a fixed distance from an injection cannula. Ma lonate (2 mu mol) caused a 23 +/- 5-fold increase in extracellular glu tamate (Glu), a 18 +/- 6-fold increase in extracellular gamma-aminobut yric acid (GABA) and a modest increase in extracellular aspartate (Asp , 2.9 +/- 0.8-fold increase). Administration of the NMDA receptor anta gonist MK-801 (5 mg/kg) prior to injection of malonate almost complete ly blocked these increases. This study provides direct evidence that i nhibition of succinate dehydrogenase causes an increase in extracellul ar amino acid neurotransmitters and further evidence that bioenergetic defects may contribute to the pathogenesis of chronic neurodegenerati ve diseases through an excitotoxic mechanism.