An evaluation of the role of extracellular amino acids in the delayed neurodegeneration induced by quinolinic acid in the rat striatum

Abstract

The effect of the N-methyl- d-aspartate receptor agonist quinolinic acid on extracellular levels of striatal amino acids, following its injection directly into the rat striatum, has been investigated using intracerebral dialysis in the attempt to elucidate the cellular mechanisms underlying delayed neurodegeneration. A neurotoxic dose (200 nmol) of quinolinic acid caused an elevation in the levels of aspartate (× 6), glutamate (× 2), asparagine (× 2), serine (× 2.5), glycine (× 3), and threonine (× 2) which peaked in the fractions 20–40 min after the injection and achieved statistical significance for aspartate and asparagine. The dialysate content of these amino acids returned to basal values within 1 h and no further changes were observed in the following 4 h. Injection of an equivalent dose of nicotinic acid did not mimic the effect of quinolinate, indicating that osmotic and/or mechanical damage was not responsible for the observed phenomena. Pretreatment with the N-methyl- d-aspartate receptor channel blocker dizocilpine (MK-801) completely blocked the quinolinate-induced increase of the amino acids, thus confirming that N-methyl- d-aspartate receptor activation is required for this effect to occur. Seven days after the injection of quinolinate, histological analysis showed an extensive loss of neuronal elements in the injected striatum, which was completely prevented in the dizocilpine-treated animals. Sections from striata of animals injected with nicotinic acid showed normal-appearing neurons and no differences were detectable from controls. Since dizocilpine can prevent striatal neurodegeneration when administered 1 h or longer after quinolinate injection [Foster et al. (1988) J. Neurosci. 8, 4745–4754], the acute changes observed in extracellular amino acid levels during the first hour after quinolinate injection seem not to be directly involved in the mechanisms of neurotoxicity.