KETAMINE INHIBITS GLUTAMATE-STIMULATED, N-METHYL-D-ASPARTATE-STIMULATED, AND QUISQUALATE-STIMULATED CGMP PRODUCTION IN CULTURED CEREBRAL NEURONS

Background: Glutamatergic signaling has been linked to the recently di scovered neurotransmitter/neuromodulator nitric oxide (NO), and severa l classes of anesthetics block some step in glutamatergic signaling. T his study was designed to determine whether or not ketamine mould prev ent NO-dependent cGMP production stimulated by glutamate (GLU) and the GLU analogs NMDA, quisqualate (QUIS), and kainate (KAIN). Methods: Pr imary cultures of cortical neurons and glia (prepared from 16-day gest ational rat fetuses) were used after 12-16 days in culture. Reactions were carried out in magnesium-free buffer containing 100 mu M 3-isobut yl-1-methylxanthine, and cGMP content of cultures was used as a bioass ay of NO production. Results: Cyclic GMP production stimulated by sodi um nitroprusside (100 mu M occurred predominately in neurons and not i n glia. Neurons were spontaneously active in these cultures; basal cGM P production was decreased by 50% in the presence of 1 mu M tetrodotox in (TTX), Glutamate (100 mu M), NMDA (100 mu M), QUIS (300 mu M), and KAIN (100 mu M) each increased cGMP content of neuronal cultures, L-NM MA (100 mu M), a NO synthase inhibitor, prevented the stimulation of c GMP production by GLU or its analogs. Pretreatment with MK-801 (1 mu M ) or ketamine (10-100 mu M) inhibited GLU-, NMDA-, and QUIS-stimulated cGMP production, Quisqualate-stimulated responses were the most sensi tive to inhibition by ketamine and NMDA-stimulated responses were the least sensitive to inhibition, MK-801 and ketamine did not significant ly inhibit KAIN-stimulated cGMP production. CNQX (10 mu m) blocked KAI N-stimulated cGMP production only. Conclusions: The authors' data demo nstrate that ketamine inhibited NO synthesis stimulated by NMDA- and n on-NMDA-receptor specific analogs. Our Endings indicate that blockade of QUIS- as well as NMDA-subtypes of GLU- receptor may be important in the development of ketamine-induced anesthesia.