Pharmahuasca and DMT Rescue ROS Production and Differentially Expressed Genes Observed after Predator and Psychosocial Stress: Relevance to Human PTSD

Post-traumatic stress
disorder (PTSD) is associated with cognitive
deficits, oxidative stress, and inflammation. Animal models have recapitulated
features of PTSD, but no comparative RNA sequencing analysis of differentially
expressed genes (DEGs) in the brain between PTSD and animal models
of traumatic stress has been carried out. We compared DEGs from the
prefrontal cortex (PFC) of an established stress model to DEGs from
the dorsolateral PFC (dlPFC) of humans. We observed a significant
enrichment of rat DEGs in human PTSD and identified 20 overlapping
DEGs, of which 17 (85%) are directionally concordant. N,N-dimethyltryptamine (DMT) is a known indirect
antioxidant, anti-inflammatory, and neuroprotective compound with
antidepressant and plasticity-facilitating effects. We tested the
capacity of DMT, the monoamine oxidase inhibitor (MAOI) harmaline,
and “pharmahuasca” (DMT + harmaline) to reduce reactive
oxygen species (ROS) production and inflammatory gene expression and
to modulate neuroplasticity-related gene expression in the model.
We administered DMT (2 mg/kg IP), harmaline (1.5 mg/kg IP), pharmahuasca,
or vehicle every other day for 5 days, following a 30 day stress regiment.
We measured ROS production in the PFC and hippocampus (HC) by electron
paramagnetic resonance spectroscopy and sequenced total mRNA in the
PFC. We also performed in vitro assays to measure
the affinity and efficacy of DMT and harmaline at 5HT2AR compared to 5-HT. DMT and pharmahuasca reduced ROS production in
the PFC and HC, while harmaline had mixed effects. Treatments normalized
9, 12, and 14 overlapping DEGs, and pathway analysis implicated that
genes were involved in ROS production, inflammation, growth factor
signaling, neurotransmission, and neuroplasticity.