Neurobiology Research Unit 8057 and The Center for Experimental Medicine Neuropharmacology, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen O, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
Biotech Research and Innovation Centre (BRIC), Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
Eur Neuropsychopharmacol. 2021 Jan;42:1-11. doi: 10.1016/j.euroneuro.2020.11.013. Epub 2020 Dec 4.
Psilocybin has in some studies shown promise as treatment of major depressive disorder and psilocybin therapy was in 2019 twice designated as breakthrough therapy by the U.S. Food and Drug Administration (FDA). A very particular feature is that ingestion of just a single dose of psilocybin is associated with lasting changes in personality and mood. The underlying molecular mechanism behind its effect is, however, unknown. In a translational pig model, we here present the effects of a single dose of psilocybin on pig behaviour, receptor occupancy and gene expression in the brain. An acute i.v. injection of 0.08 mg/kg psilocybin to awake female pigs induced characteristic behavioural changes in terms of headshakes, scratching and rubbing, lasting around 20 min. A similar dose was associated with a cerebral 5-HT receptor occupancy of 67%, as determined by positron emission tomography, and plasma psilocin levels were comparable to what in humans is associated with an intense psychedelic experience. We found that 19 genes were differentially expressed in prefrontal cortex one day after psilocybin injection, and 3 genes after 1 week. Gene Set Enrichment Analysis demonstrated that multiple immunological pathways were regulated 1 week after psilocybin exposure. This provides a framework for future investigations of the lasting molecular mechanisms induced by a single dose of psilocybin. In the light of an ongoing debate as to whether psilocybin is a safe treatment for depression and other mental illnesses, it is reassuring that our data suggest that any effects on gene expression are very modest.
裸盖菇素在一些研究中显示出治疗重度抑郁症的潜力，并且裸盖菇素疗法已于 2019 年两次被美国食品和药物管理局 (FDA) 指定为突破性疗法。一个非常特殊的特征是，摄入仅仅一剂裸盖菇素就与持久的人格和情绪变化有关。然而，其作用的潜在分子机制尚不清楚。在一个转化猪模型中，我们在此介绍了单次剂量的裸盖菇素对猪行为、大脑中受体占有率和基因表达的影响。向清醒的雌性猪静脉内急性注射 0.08mg/kg 的裸盖菇素会引起特征性的行为变化，如摇头、抓挠和摩擦，持续约 20 分钟。类似的剂量与通过正电子发射断层扫描确定的大脑 5-HT 受体占有率 67%相关，并且血浆裸盖菇素水平与在人类中与强烈的迷幻体验相关的水平相当。我们发现，在裸盖菇素注射后一天，前额叶皮层中有 19 个基因表达差异，而在 1 周后有 3 个基因表达差异。基因集富集分析表明，在暴露于裸盖菇素后 1 周，多个免疫途径受到调节。这为未来研究单次剂量的裸盖菇素引起的持久分子机制提供了框架。鉴于裸盖菇素是否是治疗抑郁症和其他精神疾病的安全治疗方法存在争议，令人欣慰的是，我们的数据表明，任何对基因表达的影响都非常轻微。
