A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT2A Receptor Density in the Pig Brain

Abstract

A single dose of psilocybin, a psychedelic and serotonin 2A receptor (5-HT2AR) 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-HT2AR. Here, we investigate if a single psychedelic dose of psilocybin changes synaptic vesicle protein 2A (SV2A) and 5-HT2AR 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 [3H]UCB-J (SV2A), [3H]MDL100907 (5-HT2AR antagonist) and [3H]Cimbi-36 (5-HT2AR agonist). One day post psilocybin injection, we observed 4.42% higher hippocampal SV2A density and lowered hippocampal and PFC 5-HT2AR density (−15.21% to −50.19%). These differences were statistically significant in the hippocampus for all radioligands and in the PFC for [3H]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-HT2AR density. Our findings suggest that psilocybin causes increased persistent synaptogenesis and an acute decrease in 5-HT2AR density, which may play a role in psilocybin’s antidepressive effects.

Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortexin vivo

“…A recent study showed that an analogue of ibogaine, a psychedelic with differing molecular targets from psilocybin, increases spine formation rate in mice (Cameron et al, 2020). Finally, in the pig, psilocybin administration was associated with higher binding of a presynaptic protein tracer in positron emission tomography (Raval et al, 2021). Although these studies provided clues linking serotonergic psychedelics to structural and functional neuroplasticity, significant gaps remain.…”

Opposite alterations of 5­HT2A receptor brain density in subjects with schizophrenia: relevance of radiotracers pharmacological profile

“…In contrast to density (B max ), the apparent affinity (K d value) was sensitive to the residual presence of antipsychotic drugs, although this effect was only observed for [ 3 H]LSD binding assays. The finding reasserts the use of agonist radiotracers to better detect the 5-HT 2A R occupation by psychedelic drugs 46 . Receptor exploration in drug-free conditions is more feasible by PET imaging than by retrospective post-mortem binding studies.…”

Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans

“…Recent work shows that a single dose of psilocybin ( 2 ) at a presumably hallucinogenic dose (0.1 mg/kg, i.v.) reduced by up to 50% the cortical abundance of 5HT 2A binding sites labelled in vitro with [ 3 H]-MDL100907 or [ 3 H]-Cimbi-36 [ 108 ]. Other examinations in the same pig brain samples with the synaptic vesicle protein 2A (SV2A) ligand [ 3 H]-UCB-J showed a significant 5–10% increase in synaptic density in hippocampus, occurring in association with the down-regulation of serotonin receptors.…”