The discriminative stimulus effects of nitrous oxidea

Abstract

Despite both widespread clinical use and a long history of abuse, there is a limited understanding of the CNS actions of the anesthetic gas nitrous oxide (N2O). In vitro data has shown that N2O oxide alters the function of NMDA and GABAA receptors, amongst others. Our overarching goal was to use drug discrimination to assess the neurotransmitter systems responsible for producing the intoxicating, subjective stimulus effects of N2O. Sixteen male B6SJLF1/J mice were trained to discriminate 10 min of exposure to 60% inhaled N2O/40% O2 versus 100% O2 in daily 5‐min operant sessions. Subsequently substitution tests with other compounds were conducted. We hypothesized that if the discriminative stimulus effects of N2O are mediated by NMDA antagonism, drugs which attenuate NMDA receptor function would substitute for N2O. Thus far the NMDA channel blockers ketamine and MK‐801 have shown partial substitution for N2O. Of 8 mice tested with ketamine, 5 fully substituted at 7 or 10 mg/kg. Of 6 mice thus far tested with MK‐801, 4 fully substituted at 0.1– 0.3 mg/kg. The NMDA competitive antagonist CGS 19755 did not substitute for N2O, producing exclusively vehicle appropriate responding in 4 of 5 mice. These results suggest the subjective stimulus properties of N2O overlap with those of noncompetitive NMDA antagonists, suggesting common underlying mechanisms of action. Supported by NIDA grant RO1‐DA020553.