Ketamine potentiates cerebrocortical damage induced by the common anaesthetic agent nitrous oxide in adult rats

1 For general anaesthesia, patients usually receive a combination of drugs, all of which are classified as gamma-amino-butyric acid (GABA) agonists, w ith two notable exceptions - ketamine and nitrous oxide (laughing gas, N2O) - which are antagonists of N-methyl-D-aspartate (NMDA) glutamate receptors . At clinically relevant doses both ketamine and N2O, like other NMDA antag onists, have the potential to induce psychotomimetic reactions in humans an d to cause pathomorphological changes in cerebrocortical neurons in rat bra in. Because drug combinations used in clinical anaesthesia sometimes includ e both ketamine and N2O, we undertook experiments to evaluate whether augme nted neurotoxicity results from their combined use. 2 Ketamine and N2O were administered alone or in combination by various dos ing regimens to adult female rats for a duration of 3 h and the severity of cerebrocortical neurotoxic changes was quantified histologically. Because GABA agonists are known to protect against the psychotomimetic and neurotox ic effects of NMDA antagonists, we also evaluated whether the combined neur otoxicity of ketamine+N2O can be prevented by certain commonly used GABA ag onists. 3 When ketamine and N2O were used in combination the neurotoxic reaction wa s enhanced to a degree much greater than can be explained by simple additiv ity. The apparent synergistic interaction was particularly striking when lo w doses of the agents were combined, the degree of toxic synergism at highe r doses being masked by a ceiling effect. GABA agonists protected against k etamine/N2O neurotoxicity. 4 It is recommended that this information be taken into consideration in th e selection of drugs to be used in multi-agent protocols for general anaest hesia.