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Journal of Neuroscience, Vol 11, 147-158, Copyright © 1991 by Society for Neuroscience
Neurochemical characterization of excitotoxin lesions in the cerebral cortex
MF Beal, KJ Swartz, SF Finn, MF Mazurek and NW Kowall
Neurochemistry Laboratory, Massachusetts General Hospital, Boston 02114.
Neuronal degeneration that occurs in both ischemia and degenerative
neurologic illnesses may involve excitotoxic mechanisms. In the present
study, we examined whether cortical lesions with agonists acting at
subtypes of glutamate receptors result in selective patterns of neuronal
death. Injections of quinolinic acid, NMDA, homocysteic acid, kainic acid
(KA), and alpha-amino-3-hydroxy-5-methylisoxazole-4- proprionic acid (AMPA)
were made at 2 sites in the dorsolateral frontoparietal cortex in rats.
After 1 week, the cerebral cortex was either dissected for neurochemical
studies, or animals were perfused for histologic evaluation. Concentrations
of somatostatin (SS), neuropeptide Y (NPY), substance P (SP),
cholecystokinin (CCK), and vasoactive intestinal polypeptide (VIP) were
measured by radioimmunoassay, while amino acids and catecholamines were
measured by high-performance liquid chromatography (HPLC) with
electrochemical detection. NMDA agonists (quinolinic acid, homocysteic
acid, and NMDA itself) resulted in dose-dependent reductions in glutamate
and GABA, while SS, NPY, SP, CCK, and VIP were either unchanged or
significantly increased in concentration. KA and AMPA at doses that
resulted in comparable GABA depletions caused significant reductions in SS
concentrations. Markers of cortical afferents were spared. All excitotoxins
resulted in dose-dependent marked increases in uric acid concentrations.
Histologic examination verified that lesions with NMDA agonists produced
relative sparing of NADPH-diaphorase, SS, VIP, and CCK neurons. These
results show that NMDA excitotoxin lesions result in a pattern of selective
neuronal damage in the cerebral cortex that is similar to that which occurs
in both ischemia and Huntington's disease.
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