A study of the role of serotonin in the anxiolytic effect of nitrous oxide in rodents.

Rationale: In earlier studies, we have shown that nitrous oxide (N2O)-induced behavioral effects in rats and mice are mediated by benzodiazepine receptors.

Objectives: This two-part study was conducted in order to investigate the possible role of serotonin (5-HT) in the behavioral effects of N2O by clarifying its effects on regional brain concentrations of 5-HT and assessing the influence of 5-HT antagonist and reuptake inhibiting drugs on the anxiolytic-like behavioral effect of N2O.

Methods: In experiment A, male, 150-200 g Sprague-Dawley rats were killed following a 15-min exposure to room air or 70% N2O. The frontal cortex, hippocampus, corpus striatum and hypothalamus were dissected out and analyzed by HPLC with electrochemical detection for content of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA); dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) were also measured. In experiment B, male 18-22 g NIH Swiss mice were pretreated with the 5-HT2 antagonist cinanserin, the 5-HT3 antagonist LY-278,584, the 5-HT reuptake inhibitor fluoxetine or saline and tested in the light/dark exploration test under 70% N2O 30 min after pretreatment.

Results: In experiment A, N2O produced differential effects on 5-HT neurons in distinct brain areas. There was increased 5-HT turnover in the hypothalamus, decreased turnover in the frontal cortex but no changes in either hippocampus or corpus striatum. By comparison, dopamine turnover in these brain regions was unaltered by N2O exposure. In experiment B, pretreatment with neither cinanserin, LY-278,584 nor fluoxetine had any appreciable effect on the N2O-induced increase in time spent in the light compartment. Only cinanserin significantly reduced the N2O-induced increase in transitions.

Conclusions: While neurochemical results suggest an effect of N2O on brain 5-HT function, there was no effect of 5-HT2 or 5-HT3 antagonists or 5-HT reuptake inhibitor on N2O-induced anxiolytic-like behavior.