A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT(2A) Receptor Density in the Pig Brain

A single dose of psilocybin, a psychedelic and serotonin 2A receptor (5-HT(2A)R) agonist, may be associated with antidepressant effects. The mechanism behind its antidepressive action is unknown but could be linked to increased synaptogenesis and down-regulation of cerebral 5-HT(2A)R. Here, we investigate if a single psychedelic dose of psilocybin changes synaptic vesicle protein 2A (SV2A) and 5-HT(2A)R density in the pig brain. Twenty-four awake pigs received either 0.08 mg/kg psilocybin or saline intravenously. Twelve pigs (n = 6/intervention) were euthanized one day post-injection, while the remaining twelve pigs were euthanized seven days post-injection (n = 6/intervention). We performed autoradiography on hippocampus and prefrontal cortex (PFC) sections with [(3)H]UCB-J (SV2A), [(3)H]MDL100907 (5-HT(2A)R antagonist) and [(3)H]Cimbi-36 (5-HT(2A)R agonist). One day post psilocybin injection, we observed 4.42% higher hippocampal SV2A density and lowered hippocampal and PFC 5-HT(2A)R density (−15.21% to −50.19%). These differences were statistically significant in the hippocampus for all radioligands and in the PFC for [(3)H]Cimbi-36 only. Seven days post-intervention, there was still significantly higher SV2A density in the hippocampus (+9.24%) and the PFC (+6.10%), whereas there were no longer any differences in 5-HT(2A)R density. Our findings suggest that psilocybin causes increased persistent synaptogenesis and an acute decrease in 5-HT(2A)R density, which may play a role in psilocybin’s antidepressive effects.