Letter to the Editor: Exposure to nitrous oxide and intrusive memory formation in psychological trauma

Das et al. (2016) conducted a study to assess the effect of nitrous oxide (N₂O) on intrusions following a traumatic event. The researchers invited 50 adult participants to watch two graphic movie scenes, followed by a 30-min exposure of either 50% gas mixture of N₂O in oxygen or medical air. Participants kept a daily record of intrusive memories for a week following the traumatic exposure. The authors noted that the incidence of intrusions decreased by as much as 50% the day after viewing in the N₂O group. However, in participants experiencing dissociation following the traumatic event, N₂O exposure produced an increased intrusion frequency. These results led the authors to conclude that N₂O may speed the decline in intrusive memory frequency following a traumatic event, presumably through its inhibitory action on central glutamatergic signaling. Though, the reverse may be true in dissociated individuals, and this finding was underemphasized by the authors, as indicated by the study's title, and the subsequent media reports commenting on the study. This concern is underscored by previous paradoxical findings on the link between subanalgesic N₂O exposure and human memory.

Ramsay et al. (1992) reported that subjects breathing N₂O required a greater number of acquisition trials to reach a learning criterion (i.e., number–noun pairs). Though N₂O exposure during acquisition of material decreased accessibility of the information, the ability to recall the material 2 weeks later improved compared with placebo. Importantly, correlational analyses suggested that this enhanced N₂O-mediated delayed recall did not appear to be dependent on the increased number of trials during acquisition in the N₂O-exposed group. Taken together, these findings suggest that N₂O exposure during acquisition or in already dissociated individuals may affect enhanced delayed recall.

In addition to the links between N₂O exposure and memory, we have proposed through repeated epidemiological investigations and review that exposure to trace levels of environmental emissions of N₂O, which, in addition to its clinical usefulness, also acts as a pervasive agricultural and combustion air pollutant, may precipitate neurodevelopmental impairment in vulnerable populations. Our epidemiological investigations to date have associated the use of nitrogen fertilizers in agriculture – as the most concentrated source of environmental N₂O emissions – with hospitalization for attention-deficit hyperactivity disorder (ADHD), representing a severely impaired phenotype (Fluegge, 2016a ; Fluegge & Fluegge, 2017). Our review of this novel hypothesis discussed the known physiological mechanisms of low-dose N₂O exposure from both in vitro and in vivo models, including disruption of the cholinergic system (Suzuki et al. 2003), endogenous release of dynorphin, and activation of the kappa opioid receptor (KOR) (Branda et al. 2000) as well as activation, at subanalgesic levels, of the corticotropin-releasing factor and brainstem noradrenergic nuclei (Zhang et al. 1999; Sawamura et al. 2003). Moreover, we cited preclinical animal studies and clinical evidence in human subjects demonstrating significant cognitive impairment and alterations in neurotransmission from trace levels of exposure to N₂O (Fluegge, 2016a ). Additionally, chronic recreational N₂O may lead to psychiatric symptoms, including dissociation (van Amsterdam et al. 2015). These specific physiological targets may directly affect attention-related neural networking as well as neural correlates of trauma-related psychopathology (Fluegge, 2016b ).

Pietrzak et al. (2014) conducted a novel brain-imaging study wherein they have linked the brain KOR to a constellation of symptoms among trauma victims. The authors administered a radioactive tracer to the KOR to all participants and compared the PET brain scans of healthy volunteers v. those clinically diagnosed with severe trauma-related psychopathology, including PTSD. Results indicated a negative correlation between KOR availability in the amygdala–anterior cingulate cortex–ventral striatal neural circuit and symptoms of loss (i.e., dysphoria), indicating that dynorphinergic excess may desensitize brain KOR, contributing to more intense dysphoric symptoms among prior trauma victims. Animal studies show that pharmacological KOR blockade administered before extinction sessions – and not before or after the conditioning – did not led to a decrease in freezing behavior in extinction sessions (Bilkei-Gorzo et al. 2012), confirming that excess dynorphinergic-mediated KOR desensitization or blockade may contribute to trauma-related psychopathology.

Chronic, intermittent exposure (i.e., 6 h/day, 5 days a week for 2 weeks) to trace levels of N₂O pollution (i.e., as low as 50 ppm, 0.005%) decreased dopamine levels in the corpus striatum of CD-1 mice (p < 0.05) (Abdul-Kareem et al. 1991). The depression in dopamine levels may be associated with compensatory increases in striatal dynorphinergic activity (Steiner & Gerfen, 1998), given the role that dynorphin opioid peptides play in N₂O-mediated antinociception especially at low doses before higher order anesthetic mechanisms are induced (Branda et al. 2000). Collectively, these studies support the hypothesis that exposure to N₂O may affect memory formation in a time and exposure-dependent manner. Importantly, though, the extent of direct modulation of opioidergic signaling (i.e., KOR desensitization) after the traumatic event due to trace environmental N₂O-mediated dynorphinergic reactivity may not only enhance delayed recall among prior trauma victims, but also facilitate co-morbid psychiatric conditions, like ADHD (Spencer et al. 2016; Fluegge, 2016b), as our prior epidemiological investigations have discussed.