Ketamine-induced anesthesia involves the [formula omitted] receptor-channel complex in mice

Abstract

The role of the N- methyl- d-aspartate (NMDA) receptor-channel complex in ketamine-induced anesthesia was examined in mice. General anesthetic potencies were evaluated on a rating scale, which provided the data for anesthetic scores, loss of righting reflex, sleeping time and recovery time. All drugs were administered intraperitoneally. NMDA (60–300 mg/kg), an NMDA receptor agonist, dose-dependently antagonized the general anesthetic potencies of ketamine at a dose of 100 mg/kg which produced loss of righting reflex in more than 90% of the mice. On the other hand, a high dose of N- methyl- l-aspartate (400 mg/kg), a stereoisomer of NMDA, did not. A dose of 300 mg/kg of NMDA significantly shifted the dose-response curve of ketamine for loss of righting reflex to the right. A high dose of d-cycloserine (200 mg/kg), an agonist at the glycine site on the NMDA receptor complex, slightly but significantly shortened the sleeping time caused by ketamine (100 mg/kg). However, neither a critical subconvulsive dose of kainate (15 mg/kg), a kainate receptor agonist, nor a subsconvulsive dose of quisqualate (120 mg/kg), an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor agonist, reversed general anesthesia induced by 100 mg/kg of ketamine. Both the competitive NMDA antagonist, (±)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP; 10–30 mg/kg), and the non-competitive NMDA antagonist, MgCl 2 (30–120 mg/kg), dose-dependently potentiated the anesthetic actions induced by a lower dose of ketamine (70 mg/kg) which produced loss of righting reflex in less than 20% of the mice, but (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine hydrogen maleate (MK-801; 0.3–3.0 mg/kg), another potent non-competitive NMDA antagonist, did not. However, pretreatment with a low dose of haloperidol (0.1 mg/kg), a dopamine receptor antagonist, along with 0.3 mg/kg of MK-801 (which in itself elicited only stimulant actions), significantly increased the anesthetic potencies of ketamine at 70 mg/kg. Pharmacokinetic studies revealed that NMDA (300 mg/kg) and CPP (30 mg/kg) did not significantly alter the level of ketamine in the brain. These results suggest that ketamine-induced anesthesia is mediated, at least in part, by the NMDA receptor-channel complex.