A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT2A Receptor Density in the Pig Brain
Nakul Ravi Raval, Annette Johansen, Lene Lundgaard Donovan, Nídia Fernandez Ros, Brice Ozenne, Hanne D. Hansen, Gitte M. Knudsen
International Journal of Molecular Sciences January 15, 2021 DOI: 10.3390/ijms22020835 via OpenAlex
Summary
AI-generated from the abstractA single psychedelic dose of psilocybin increases synaptic density and temporarily reduces serotonin 2A receptor density in the pig brain. One day after injection, hippocampal synaptic vesicle protein 2A (SV2A) density was 4.42% higher, while hippocampal and prefrontal cortex 5-HT2AR density dropped by 15.21% to 50.19%. Seven days later, SV2A density remained significantly higher in the hippocampus (+9.24%) and prefrontal cortex (+6.10%), but 5-HT2AR density had returned to baseline. These persistent synaptic changes and acute receptor down-regulation may underlie psilocybin’s antidepressant effects.
Study at a glance
| Characteristics | Randomized controlled trial Peer reviewed |
|---|---|
| Sample size | 24 |
| Population | Awake pigs |
| Intervention | Psilocybin |
| Dose | 0.08 mg/kg |
| Duration | One day and seven days post-injection |
| Topics | Psilocybin |
| Keywords | Neuroscience Hallucinogen Chemistry Pharmacology |
| Citations | 191 |
| Key finding | A single dose of psilocybin increased synaptic density persistently and decreased serotonin 2A receptor density acutely 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.