ACTIVATION OF GLUTAMATERGIC NEUROTRANSMISSION BY KETAMINE - A NOVEL STEP IN THE PATHWAY FROM NMDA RECEPTOR BLOCKADE TO DOPAMINERGIC AND COGNITIVE DISRUPTIONS ASSOCIATED WITH THE PREFRONTAL CORTEX

Subanesthetic doses of ketamine, a noncompetitive NMDA receptor antago nist, impair prefrontal cortex (PFC) function in the rat and produce s ymptoms in humans similar to those observed in schizophrenia and disso ciative states, including impaired performance of frontal robe-sensiti ve tests. Several lines of evidence suggest that ketamine may impair P FC function in part by interacting with dopamine neurotransmission in this region. This study sought to determine the mechanism by which ket amine may disrupt dopaminergic neurotransmission in, and cognitive fun ctions associated with, the PFC. A thorough dose-response study using microdialysis in conscious rats indicated that low doses of ketamine ( 10, 20, and 30 mg/kg) increase glutamate outflow in the PFC, suggestin g that at these doses ketamine may increase glutamatergic neurotransmi ssion in the PFC at non-NMDA glutamate receptors. An anesthetic dose o f ketamine (200 mg/kg) decreased, and an intermediate dose of 50 mg/kg did not affect, glutamate levels. Ketamine, at 30 mg/kg, also increas ed the release of dopamine in the PFC. This increase was blocked by in tra-PFC application of the AMPA/kainate receptor antagonist, 6-cyano-7 -nitroquinoxaline-2,3-dione CNQX. Furthermore, ketamine-induced activa tion of dopamine release and impairment of spatial delayed alternation in the rodent, a PFC-sensitive cognitive task, was ameliorated by sys temic pretreatment with AMPA/kainate receptor antagonist LY293558. The se findings suggest that ketamine may disrupt dopaminergic neurotransm ission in the PFC as well as cognitive functions associated with this region, in part, by increasing the release of glutamate, thereby stimu lating postsynaptic non-NMDA glutamate receptors.