Psilocybin restores behavior and 5-HT2A signaling while reducing microglial density after chronic traumatic brain injury in rats

Allen, J; Jupp, B; Baker, TL; Haskali, MB; Brkljača, R; Plummer, Z; Sun, M; Brand, J; Christie, BR; Debert, CT; McDonald, SJ; O&#39;Brien, TJ; Casillas-Espinosa, PM; Shultz, SR

Author(s): Allen, J; Jupp, B; Baker, TL; Haskali, MB; Brkljača, R; Plummer, Z; Sun, M; Brand, J; Christie, BR; Debert, CT; McDonald, SJ; O'Brien, TJ; Casillas-Espinosa, PM; Shultz, SR;
Details: Publication Year 2026-07-21,Volume 7,Issue #7,Page 102867
Journal Title: Cell Reports Medicine
Publication Type: Research article
Abstract: Traumatic brain injury (TBI) causes persistent neurobehavioral deficits and increases the risk of psychiatric disorders, including depression, anxiety, and cognitive dysfunction linked to disrupted neuroplasticity, neuroinflammation, and serotonergic (5-HT) signaling. No effective pharmacotherapies exist for chronic TBI. Psilocybin, a psychedelic 5-HT(2A) receptor agonist, shows promise due to its neuroplasticity-enhancing, anti-inflammatory, and antidepressant effects. Here, male rats received fluid-percussion or sham injury, followed one year later by a single psilocybin (1 mg/kg) or saline injection. Behavioral testing began 24 h later, and positron emission tomography assessed 5-HT(2A) binding after two weeks. TBI produced persistent sensorimotor, learning and memory, and affective deficits; reduced 5-HT(2A) binding; and microglial alterations in the medial prefrontal cortex characterized by decreased process branching and enlarged soma size. Psilocybin treatment could improve sensorimotor function, restore 5-HT(2A) binding, and reduce microglial cell counts. These findings highlight psilocybin's therapeutic potential in chronic TBI and support further investigation of psychedelic treatments.
Publisher: Cell Press
Keywords: Animals; *Microglia/drug effects/metabolism/pathology; *Brain Injuries, Traumatic/drug therapy/metabolism/pathology; Male; *Receptor, Serotonin, 5-HT2A/metabolism; Rats; *Signal Transduction/drug effects; *Psilocybin/pharmacology/therapeutic use; *Behavior, Animal/drug effects; Rats, Sprague-Dawley; Iba1; Pet; concussion; fluid-percussion injury; microglia; positron emission tomography; psychedelic; serotonin receptor
Department(s): Cancer Imaging
Publisher's Version: https://doi.org/10.1016/j.xcrm.2026.102867
Open Access at Publisher's Site: https://doi.org/10.1016/j.xcrm.2026.102867
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-06-25 06:02:47

Last Modified: 2026-08-11 02:01:18