Pharmacological elevation of endogenous kynurenic acid levels activates nigral dopamine neurons

Inhibitors of kynurenine 3-hydroxylase have previously been used to increase endogenous levels of kynurenic acid, an excitatory amino acid receptor antagonist. In the present electrophysiological study PNU 156561A was utilized to elevate endogenous concentrations of kynurenic acid and subsequent effects 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 brain five to seven hours after administration and also evoked a significant increase in firing rate and bursting activity of nigral DA neurons. The results of the present study show that a moderate increase in endogenous kynurenic acid levels produces significant actions on the tonic glutamatergic control of the firing pattern of nigral DA neurons, and implicate kynurenine 3-hydroxylase inhibitors as novel antiparkinsonian agents.