Nitrous oxide (N2O) gas is a widely used anesthetic adjunct in dentistry and medicine that is also commonly abused. Studies have shown that N2O alters the function of the NMDA, GABAA, opioid and serotonin receptors among others. However the receptors systems underlying the abuse-related CNS effects of N2O are unclear. The goal of this study was to explore the receptor systems responsible for producing the discriminative stimulus effects of N2O. B6SJLF1/J male mice previously trained to discriminate 10 min of exposure to 60% N2O+40% oxygen versus 100% oxygen in a two-lever food reinforced operant task served as subjects. Both the high affinity NMDA receptor channel blocker (+)-MK-801 and the low affinity blocker memantine partially mimicked the stimulus effects of N2O. Neither the competitive NMDA antagonist, CGS-19755 nor the NMDA glycine-site antagonist, L701-324 produced N2O-like stimulus effects. A range of GABAA agonists and positive modulators including midazolam, pentobarbital, muscimol and gaboxadol all failed to produce N2O-like stimulus effects. Mu, kappa and delta opioid agonists as well as 5-HT1B/2C and 5-HT1A agonists also failed to produce N2O-like stimulus effects. Ethanol partially substituted for N2O. Both (+)-MK-801 and ethanol but not midazolam pretreatment also significantly enhanced the discriminative stimulus effects of N2O. The present results support the hypothesis that the discriminative stimulus effects of N2O are at least partially mediated by NMDA antagonist effects similar to those produced by channel blockers. However, as none of the drugs tested fully mimicked the stimulus effects of N2O, other mechanisms may also be involved.
- The American Society for Pharmacology and Experimental Therapeutics