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 discovered neurotransmitter/neuromodulator nitric oxide (NO), and several classes of anesthetics block some step in glutamatergic signaling. This study was designed to determine whether or not ketamine mould prevent NO-dependent cGMP production stimulated by glutamate (GLU) and the GLU analogs NMDA, quisqualate (QUIS), and kainate (KAIN). Methods: Primary cultures of cortical neurons and glia (prepared from 16-day gestational rat fetuses) were used after 12-16 days in culture. Reactions were carried out in magnesium-free buffer containing 100 mu M 3-isobutyl-1-methylxanthine, and cGMP content of cultures was used as a bioassay of NO production. Results: Cyclic GMP production stimulated by sodium nitroprusside (100 mu M occurred predominately in neurons and not in glia. Neurons were spontaneously active in these cultures; basal cGMP production was decreased by 50% in the presence of 1 mu M tetrodotoxin (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-NMMA (100 mu M), a NO synthase inhibitor, prevented the stimulation of cGMP 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 sensitive to inhibition by ketamine and NMDA-stimulated responses were the least sensitive to inhibition, MK-801 and ketamine did not significantly inhibit KAIN-stimulated cGMP production. CNQX (10 mu m) blocked KAIN-stimulated cGMP production only. Conclusions: The authors' data demonstrate that ketamine inhibited NO synthesis stimulated by NMDA- and non-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.