Psychedelics promote plasticity by directly binding to BDNF receptor TrkB

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

doi:10.1038/s41593-023-01316-5

Psychedelics promote plasticity by directly binding to BDNF receptor TrkB

Rafael Moliner, Mykhailo Girych, Cecilia A. Brunello, Vera Kovaleva, Caroline Biojone, Giray Enkavi, Lina Antenucci, Erik F. Kot, Sergey A. Goncharuk, Katja Kaurinkoski, Mirjami Kuutti, Senem M. Fred, Lauri V. Elsilä, Sven Sakson, Cecilia Cannarozzo, Cassiano R.A.F. Diniz, Nina Seiffert, Anna Rubiolo, Hele Haapaniemi, Elsa MeshiElina Nagaeva, Tiina Öhman, Tomasz Róg, Esko Kankuri, Marçal Vilar, Markku Varjosalo, Esa R. Korpi, Perttu Permi, Konstantin S. Mineev, Mart Saarma, Ilpo Vattulainen^*, Plinio C. Casarotto^*, Eero Castrén^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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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-HT_2A) activation, whereas LSD-induced head twitching is dependent on 5-HT_2A 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-HT_2A activity may retain the antidepressant potential of psychedelics without hallucinogenic effects.

Original language	English
Journal	Nature Neuroscience
Volume	26
Issue	6
Pages (from-to)	1032-1041
Number of pages	10
ISSN	1097-6256
DOIs	https://doi.org/10.1038/s41593-023-01316-5
Publication status	Published - Jun 2023

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Moliner, R., Girych, M., Brunello, C. A., Kovaleva, V., Biojone, C., Enkavi, G., Antenucci, L., Kot, E. F., Goncharuk, S. A., Kaurinkoski, K., Kuutti, M., Fred, S. M., Elsilä, L. V., Sakson, S., Cannarozzo, C., Diniz, C. R. A. F., Seiffert, N., Rubiolo, A., Haapaniemi, H., ... Castrén, E. (2023). Psychedelics promote plasticity by directly binding to BDNF receptor TrkB. Nature Neuroscience, 26(6), 1032-1041. https://doi.org/10.1038/s41593-023-01316-5

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title = "Psychedelics promote plasticity by directly binding to BDNF receptor TrkB",

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.",

author = "Rafael Moliner and Mykhailo Girych and Brunello, {Cecilia A.} and Vera Kovaleva and Caroline Biojone and Giray Enkavi and Lina Antenucci and Kot, {Erik F.} and Goncharuk, {Sergey A.} and Katja Kaurinkoski and Mirjami Kuutti and Fred, {Senem M.} and Elsil{\"a}, {Lauri V.} and Sven Sakson and Cecilia Cannarozzo and Diniz, {Cassiano R.A.F.} and Nina Seiffert and Anna Rubiolo and Hele Haapaniemi and Elsa Meshi and Elina Nagaeva and Tiina {\"O}hman and Tomasz R{\'o}g and Esko Kankuri and Mar{\c c}al Vilar and Markku Varjosalo and Korpi, {Esa R.} and Perttu Permi and Mineev, {Konstantin S.} and Mart Saarma and Ilpo Vattulainen and Casarotto, {Plinio C.} and Eero Castr{\'e}n",

year = "2023",

month = jun,

doi = "10.1038/s41593-023-01316-5",

language = "English",

volume = "26",

pages = "1032--1041",

journal = "Nature Neuroscience",

issn = "1097-6256",

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Moliner, R, Girych, M, Brunello, CA, Kovaleva, V, Biojone, C, Enkavi, G, Antenucci, L, Kot, EF, Goncharuk, SA, Kaurinkoski, K, Kuutti, M, Fred, SM, Elsilä, LV, Sakson, S, Cannarozzo, C, Diniz, CRAF, Seiffert, N, Rubiolo, A, Haapaniemi, H, Meshi, E, Nagaeva, E, Öhman, T, Róg, T, Kankuri, E, Vilar, M, Varjosalo, M, Korpi, ER, Permi, P, Mineev, KS, Saarma, M, Vattulainen, I, Casarotto, PC & Castrén, E 2023, 'Psychedelics promote plasticity by directly binding to BDNF receptor TrkB', Nature Neuroscience, vol. 26, no. 6, pp. 1032-1041. https://doi.org/10.1038/s41593-023-01316-5

TY - JOUR

T1 - Psychedelics promote plasticity by directly binding to BDNF receptor TrkB

AU - Moliner, Rafael

AU - Girych, Mykhailo

AU - Brunello, Cecilia A.

AU - Kovaleva, Vera

AU - Biojone, Caroline

AU - Enkavi, Giray

AU - Antenucci, Lina

AU - Kot, Erik F.

AU - Goncharuk, Sergey A.

AU - Kaurinkoski, Katja

AU - Kuutti, Mirjami

AU - Fred, Senem M.

AU - Elsilä, Lauri V.

AU - Sakson, Sven

AU - Cannarozzo, Cecilia

AU - Diniz, Cassiano R.A.F.

AU - Seiffert, Nina

AU - Rubiolo, Anna

AU - Haapaniemi, Hele

AU - Meshi, Elsa

AU - Nagaeva, Elina

AU - Öhman, Tiina

AU - Róg, Tomasz

AU - Kankuri, Esko

AU - Vilar, Marçal

AU - Varjosalo, Markku

AU - Korpi, Esa R.

AU - Permi, Perttu

AU - Mineev, Konstantin S.

AU - Saarma, Mart

AU - Vattulainen, Ilpo

AU - Casarotto, Plinio C.

AU - Castrén, Eero

PY - 2023/6

Y1 - 2023/6

N2 - 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.

AB - 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.

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U2 - 10.1038/s41593-023-01316-5

DO - 10.1038/s41593-023-01316-5

M3 - Journal article

C2 - 37280397

AN - SCOPUS:85161237972

SN - 1097-6256

VL - 26

SP - 1032

EP - 1041

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 6

ER -

Psychedelics promote plasticity by directly binding to BDNF receptor TrkB

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