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

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-HT2A 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-HT2A binding after two weeks. TBI produced persistent sensorimotor, learning and memory, and affective deficits; reduced 5-HT2A 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-HT2A binding, and reduce microglial cell counts. These findings highlight psilocybin's therapeutic potential in chronic TBI and support further investigation of psychedelic treatments.