Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 27 November 2020 / Approved: 30 November 2020 / Online: 30 November 2020 (16:30:03 CET)

A peer-reviewed article of this Preprint also exists.

Raval, N.R.; Johansen, A.; Donovan, L.L.; Ros, N.F.; Ozenne, B.; Hansen, H.D.; Knudsen, G.M. A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT2A Receptor Density in the Pig Brain. Int. J. Mol. Sci. 2021, 22, 835. Raval, N.R.; Johansen, A.; Donovan, L.L.; Ros, N.F.; Ozenne, B.; Hansen, H.D.; Knudsen, G.M. A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT2A Receptor Density in the Pig Brain. Int. J. Mol. Sci. 2021, 22, 835.

Journal reference: Int. J. Mol. Sci. 2021, 22, 835
DOI: 10.3390/ijms22020835

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 4.4% 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 PFC for [3H]Cimbi-36 only. Seven days post-intervention, there was still significantly higher SV2A density in hippocampus (+9.24%) and PFC (+6.1%) whereas there were no longer any differences in 5-HT2AR density. Our findings suggest that psilocybin’s antidepressive actions are linked to increased persistent synaptogenesis and possibly also to an acute decrease in 5-HT2AR density.

Subject Areas

Psilocybin; psychedelics; neuroplasticity; SV2A; 5-HT2A; depression; autoradiography; functional-selectivity

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