Nitrous Oxide-induced Impairment of Spatial Working Memory Requires Activation of GABAergic Pathways

Background: Previous research from our laboratory implicated opioid and benzodiazepine- GABA mechanisms in other effects of N2O (antinociception and anxiolysis), so a decision was made to study these as potential mechanisms of N2O-induced dysfunction of spatial working memory. Objective: to explore potential mechanisms of N2O in reducing spatial working memory in mice. Methods: we monitored spontaneous alternation behavior (SAB) in male NIH Swiss mice exposed to N2O during a T-maze spontaneous alternation task (T-SAT). Results: mice that were exposed to 70% N2O (in O2) exhibited severely and significantly reduced spontaneous alternation behavior in the T-SAT. Mice in this environment alternated their route only 33% of the time, in comparison to the control (room air) rate of alternation at approximately 70%. Mice pretreated with the benzodiazepine antagonist, flumazenil exhibited a dose-dependent restoration of spatial working memory under 70% N2O in the T-SAT. Alternatively, pretreatment with neither the GABAA antagonist gabazine nor the opioid antagonist naloxone had any appreciable effect on the N2O-reduced SAB. Conclusion: this study verified that 70% N2O can reduce spatial working memory in mice, which appears to involve benzodiazepine mechanisms in the brain.