Duplication of biochemical changes of Huntington's chorea by intrastriatal injections of glutamic and kainic acids

Abstract

SYSTEMIC administration of large doses of L-glutamate to immature animals causes degeneration of neurones in the retina and the arcuate nucleus. Olney et al.¹ reported that intracerebral injections of the more potent excitatory analogues of glutamate, in particular kainic acid, caused rapid degeneration of certain dendritic and somal structures in the injected area. Presumably the degeneration is related to the ability to bind the ‘excitotoxic’ agent, with necrosis resulting from a sustained increase in membrane permeability. ³H-kainic acid binds more strongly to striatal tissue than to any other area of rat brain tested². This lends some support to Spencer's theory³—based on antagonism of cortical excitation of striatal neurones by diethyl glutamate—that the massive corticostriatal pathway is glutaminergic. If Huntington's chorea were an excitotoxic phenomenon resulting from chronic overstimulation of glutamate receptors, striatal neurones in particular would be affected because of heavy glutaminergic input. This hypothesis is not readily tested by simple measurement of glutamate in choreic tissue because glutamate is a precursor of γ-aminobutyric acid (GABA) and is also involved in other metabolic activities. As one potential test of this hypothesis, we have injected 1 µl of either kainic acid or L-glutamic acid dissolved in isotonic saline directly into the extrapyramidal nuclei of rats. Injection into the striatum produced local enzymatic changes duplicating those reported in Huntington's chorea.