Pharmacological elevation of endogenous kynurenic acid levels activates nigral dopamine neurons

Inhibitors of kynurenine 3-hydroxylase have previously been used to increas e endogenous levels of kynurenic acid, an excitatory amino acid receptor an tagonist. In the present electrophysiological study PNU 156561A was utilize d to elevate endogenous concentrations of kynurenic acid and subsequent eff ects on the firing pattern of dopamine (DA) neurons of rat substantia nigra (SN) were analyzed. Pretreatment with PNU 156561A (40 mg/kg, i.v., 5-7 h) caused a five-fold increase in endogenous kynurenic acid levels in whole br ain five to seven hours after administration and also evoked a significant increase in firing rate and bursting activity of nigral DA neurons. The res ults of the present study show that a moderate increase in endogenous kynur enic acid levels produces significant actions on the tonic glutamatergic co ntrol of the firing pattern of nigral DA neurons, and implicate kynurenine 3-hydroxylase inhibitors as novel antiparkinsonian agents.