Intracerebral quinolinic acid injection in the rat: effects on dopaminergic neurons

Abstract

Intrastriatal infusion of the endogenous excitotoxin quinolinic acid (QUIN) leads to the degeneration of neuronal cell bodies around the injection site. Dopaminergic afferents not only survive the toxic insult but react by increasing their activity in the acute and subacute phases following the injection of QUIN. Measurements of the tissue concentrations of acidic dopamine metabolites, and determinations of L-DOPA accumulation after DOPA-decarboxylase inhibition, indicate an increased dopamine turnover within 90 min after the administration of 50 micrograms QUIN. At the later timepoints examined (6 h, 4 and 11 days after QUIN), dopaminergic parameters are increased in the injected striatum only while no changes can be detected in the homolateral substantia nigra. Local norepinephrine levels are elevated 4 and 11 days after an intrastriatal QUIN injection but remain unchanged at distant sites or earlier postinjection periods. The acute increase in nigrostriatal activity may be mediated by an excessively stimulated, yet functional striatonigral feedback loop whereas subsequent changes represent local reactions of dopaminergic nerve terminals secondary to neuronal degeneration in the striatum. In accordance with this interpretation, no monoaminergic changes can be observed in the hypothalamus 4 days following the local injection of 50 micrograms QUIN, a dose which does not cause neuronal necrosis in this brain area. These data are concordant with, and are discussed in the context of, a possible involvement of QUIN in the pathogenesis of Huntington's disease.