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Serotonin 5-HT2A receptor expression is chronically decreased in the anterior cerebral cortex of male rats following repetitive low-level blast exposure

Summary

Military Veterans exposed to blast explosions often develop long-term problems with memory, anxiety, and PTSD. Researchers found that in rats exposed to blast, a brain receptor called 5-HT2A becomes less active, particularly in the front part of the brain involved in thinking and emotions. This decrease in the receptor correlates with anxiety-like behaviors in the animals. Since psychedelic substances like psilocybin activate this same receptor, the findings suggest that such substances might help treat PTSD and cognitive problems in blast-injured Veterans.

Background

Veterans exposed to blast-related traumatic brain injuries (TBIs) in Iraq and Afghanistan often suffer from chronic cognitive and mental health problems including depression and post-traumatic stress disorder (PTSD). Male rats exposed to repetitive low-level blast have been shown to develop chronic cognitive and PTSD-related behavioral traits lasting over one year after exposure. Psychedelic agents like psilocybin, which stimulate serotonin 2A receptors (5-HT2AR), are gaining attention as potential treatments for Veterans with mental health disorders.

Objective

This study aimed to determine whether 5-HT2AR levels are altered by blast exposure in a rat model of blast-induced TBI. The researchers examined 5-HT2AR expression across multiple time points (2 weeks to 12 months post-blast) in three brain regions relevant to fear learning and PTSD pathology: anterior cerebral cortex, hippocampus, and amygdala.

Results

5-HT2AR expression was chronically decreased in the anterior cortex of blast-exposed rats in all cohorts except the one studied at 2 weeks after blast exposure, with levels steadily decreasing over time. 5-HT2AR levels were more variably affected in hippocampus and amygdala across cohorts. Decreased 5-HT2AR expression in anterior cortex correlated with blast-induced behavioral changes including increased freezing in fear conditioning and altered responses in novel object recognition and elevated zero maze tasks.

Conclusion

These findings demonstrate that 5-HT2AR expression is chronically decreased in the anterior cerebral cortex following blast exposure, suggesting 5-HT2AR as a potential therapeutic target for treatment of PTSD-related symptoms following blast injury. The results have implications for understanding the neurochemical basis of blast-induced cognitive and behavioral changes and support investigation of agents targeting 5-HT2AR, such as psilocybin, for treating Veterans with blast-related TBI and PTSD.
  • Published in:Frontiers in Neurology,
  • Study Type:Animal Model Study,
  • Source: PMID: 40635716, DOI: 10.3389/fneur.2025.1594335
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