小柯机器人

芬兰赫尔辛基大学Eero Castrén，Plinio C. Casarotto和Ilpo Vattulainen共同合作，近期取得重要工作进展。他们研究发现致幻剂可以通过直接结合BDNF受体TrkB来促进神经可塑性。相关研究成果2023年6月5日在线发表于《自然—神经科学》杂志上。

据介绍，迷幻药产生快速而持久的抗抑郁作用，并诱导类似于临床批准的抗抑郁药的神经可塑性。研究人员最近报道了药理学上多种抗抑郁药，包括氟西汀和氯胺酮，通过与BDNF受体TrkB结合发挥作用。

研究人员发现，麦角酸二乙酰胺（LSD）和裸盖菌素直接与TrkB结合，其亲和力是其它抗抑郁药的1000倍，迷幻药和抗抑郁药与TrkB二聚体跨膜结构域内不同但部分重叠的位点结合。迷幻药对小鼠神经营养信号传导、可塑性和抗抑郁样行为的影响取决于TrkB的结合和内源性BDNF信号传导的促进，但不依赖于血清素2A受体（5-HT_2A）的激活，而LSD诱导的头部抽搐依赖于5-HT_2A，不依赖于TrkB的结合。

总之，这一研究数据证实了TrkB是抗抑郁药的常见主要靶点，并表明缺乏5-HT_2A活性的高亲和力TrkB阳性变构调节剂可能保留了迷幻药的抗抑郁潜力，且没有致幻作用。

附：英文原文

Title: Psychedelics promote plasticity by directly binding to BDNF receptor TrkB

Author: Moliner, Rafael, Girych, Mykhailo, Brunello, Cecilia A., Kovaleva, Vera, Biojone, Caroline, Enkavi, Giray, Antenucci, Lina, Kot, Erik F., Goncharuk, Sergey A., Kaurinkoski, Katja, Kuutti, Mirjami, Fred, Senem M., Elsil, Lauri V., Sakson, Sven, Cannarozzo, Cecilia, Diniz, Cassiano R. A. F., Seiffert, Nina, Rubiolo, Anna, Haapaniemi, Hele, Meshi, Elsa, Nagaeva, Elina, hman, Tiina, Rg, Tomasz, Kankuri, Esko, Vilar, Maral, Varjosalo, Markku, Korpi, Esa R., Permi, Perttu, Mineev, Konstantin S., Saarma, Mart, Vattulainen, Ilpo, Casarotto, Plinio C., Castrn, Eero

Issue&Volume: 2023-06-05

Abstract: Psychedelics produce fast and persistent antidepressant effects and induce neuroplasticity resembling the effects of clinically approved antidepressants. We recently reported that pharmacologically diverse antidepressants, including fluoxetine and ketamine, act by binding to TrkB, the receptor for BDNF. Here we show that lysergic acid diethylamide (LSD) and psilocin directly bind to TrkB with affinities 1,000-fold higher than those for other antidepressants, and that psychedelics and antidepressants bind to distinct but partially overlapping sites within the transmembrane domain of TrkB dimers. The effects of psychedelics on neurotrophic signaling, plasticity and antidepressant-like behavior in mice depend on TrkB binding and promotion of endogenous BDNF signaling but are independent of serotonin 2A receptor (5-HT2A) activation, whereas LSD-induced head twitching is dependent on 5-HT2A and independent of TrkB binding. Our data confirm TrkB as a common primary target for antidepressants and suggest that high-affinity TrkB positive allosteric modulators lacking 5-HT2A activity may retain the antidepressant potential of psychedelics without hallucinogenic effects. Moliner et al. show that psychedelics directly bind to the BDNF receptor TrkB with high affinity and promote BDNF-mediated plasticity and antidepressant-like effects, whereas their hallucinogenic-like effects are independent of TrkB binding.

DOI: 10.1038/s41593-023-01316-5

Source: https://www.nature.com/articles/s41593-023-01316-5

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex