Subchronic treatment with kynurenine and probenecid: effects on prepulse inhibition and firing of midbrain dopamine neurons

Acute elevation of the endogenous NMDA-receptor antagonist kynurenic acid (KYNA) is associated with an increased neuronal activity of rat ventral tegmental area (VTA) dopamine (DA) neurons and disruption in prepulse inhibition (PPI). In the present study, the effects of subchronic exposure to kynurenine and probenecid (20 mg/kg/day and 10 mg/kg/day, respectively for 14 days), aiming at increasing brain KYNA turnover, on rat VTA dopaminergic firing and on PPI were investigated. This treatment increased neuronal firing of VTA DA neurons, changed the response of these neurons to systemically administered nicotine (3-400 mu g/kg, i.v.) and tended to disrupt PPI. Present results show that the effect on firing of VTA DA neurons by acutely elevated levels of brain KYNA also persists following subchronic exposure. In addition, no adaptive changes seem to occur with regard to the electrophysiological effects of KYNA on VTA DA neurons following subchronic treatment with kynurenine and probenecid.