Previous studies have shown that systemically administered nicotine is associated with an activation of rat midbrain dopamine neurons. The aim of the present electrophysiological study was to investigate if manipulation of brain kynurenic acid, an endogenous excitatory amino acid receptor antagonist, can affect the response of nigral dopamine neurons to nicotine. A potent inhibitor of kynurenine 3-hydroxylase, PNU 156561A (40 mg/kg, i.v., 4-7 h), was utilized to increase the levels of kynurenic acid in rat brain. This treatment, which caused a fourfold increase in brain kynurenic acid levels, abolished the increase in firing rate and burst activity of nigral dopamine neurons as induced by nicotine (25-400 microg/kg, i.v.). It is proposed that the excitation of dopamine neurons in the substantia nigra following nicotine administration is an indirect effect, mediated by glutamate release. In addition, our data highlight the role of brain kynurenic acid as a potentially important modulator of basic glutamatergic responses in brain.