THE 1993 UPJOHN AWARD LECTURE - QUINOLINIC ACID-INDUCED BRAIN NEUROTRANSMITTER DEFICITS - MODULATION BY ENDOGENOUS EXCITOTOXIN ANTAGONISTS

Excitotoxins constitute a group of agents that are capable of activati ng excitatory amino acid receptors and producing axon-sparing neuronal lesions. Focal injections of the exogenous excitotoxins kainic acid a nd ibotenic acid result in depletion of neurotransmitter markers in ne uronal cell bodies located in areas of injection or in terminal zones of their projections. The discovery of endogenous agents that behave a s excitotoxins has generated interest in the idea that excitotoxicity may contribute to the neuronal degeneration associated with a number o f neurological diseases (Alzheimers's disease, Huntington's disease, P arkinson's disease) which involve selective neurotransmitter deficits. Quinolinic acid (QUIN), a pyridine dicarboxylic acid and metabolite o f tryptophan, which has been detected in the central nervous system (C NS), behaves as an excitotoxin. In the mammalian brain QUIN has ben lo calized to glial and immune cells, and its content increases with age. The neuroexcitatory and neurotoxic actions of QUIN are mediated via t he MG(2+)-sensitive N-methyl-D-asparate (NMDA) receptor. The toxicity of QUIN, like that of kainate, but not ibotenate, is dependent on the presence of an intact glutamate-aspartate afferent input to the target area. Focal injections QUIN into the nucleus basalis megnocellularis (nbM), a major source of cholinergic innervation to diencephalic areas , produce sustained loss of cholinergic neuron markers in the neocorte x and amygdala. The neurotoxic action of QUIN on nbM results in an imp airment of performance on memory-related tasks. Cortical and amygdaloi d projecting cholinergic neurons show differential sensitivity to QUIN and other excitotoxic agents. This factor may partly explain the repo rted discrepancy between mnemonic deficits and the loss of cholinergic markers in the cerebral cortex induced by intra-nbM injections of cer tain excitotoxins. Cortical muscarinic receptor function is not signif icantly influenced by QUIN injections into the nbM producing loss of c ortical cholinergic neurons. In the striatum, focal QUIN injections ha ve been found to largely replicate the neurotransmitter deficits preva iling in Huntingtons's disease, an inherited movement disorder. Intras triatal QUIN produces a profound loss of the NADPH diaphorase staining neurons in the area of injection but relatively spares these in the a djacent transition zone. QUIN is also highly damaging to the striatopa llidal enkephalinergic neurons. However, at doses that are neurotoxic to striatal neurons, QUIN and several other excitotoxins produce signi ficant elevations in enkephalin levels both in the striatum and globus pallidus. This elevation reflects the presence of a plasticity in the striatal enkephalinergic neuron population. The metabolic pathway yie lding QUIN produces a number of intermediates that act as excitotoxin antagonists. Kynurenic acid, the most potent of these endogenous agent s, blocks the action of QUIN and other excitotoxins that act on NMDA a nd non-NMDA receptors. Picolinic acid, a pyridine monocarboxylic acid, also attenuates QUIN toxicity. However, it only influences excitotoxi ns that require an intact glutamatergic afferent input to the target a rea for the expression of their neurotoxic action. Although picolinic acid modulates presynaptic glutamate release in vitro, this action doe s not entirely explain its restricted anti-excitotoxic action. The pre sence of several endogenous excitotoxin antagonists in the CNS has imp ortant implications for neuron survival. A balance between endogenous excitotoxins and their built-in antagonists may influence the viabilit y of neuronal groups in the CNS. It also suggests a novel strategy for influencing excitotoxicity through elevations in levels of endogenous antagonists. Nicotinylalamine, an enzyme inhibitor, elevates brain ky nurenate levels and exhibits potential for anticonvulsant and anti-exc itotoxic action. The study of QUIN and related agents holds promise of understanding factors that underlie neuronal damage and developing no vel agents to reduce or prevent this damage in areas of the cns affect ed in neurodegenerative disease.