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<p>Nonhallucinogenic psychoplastogens, such as tabernanthalog (TBG), are being developed as potentially safer, more scalable alternatives to psychedelics for promoting neuronal growth and treating various brain conditions. Currently, it is unclear whether 5-hydroxytryptamine 2A (5-HT<sub>2A</sub>) receptors and immediate early gene (IEG) activation have a role in the neuroplasticity-promoting effects of nonhallucinogenic psychoplastogens. Here, we use pharmacological and genetic tools in rodents to show that nonhallucinogenic psychoplastogens promote cortical neuroplasticity through the same biochemical pathway—involving 5-HT<sub>2A</sub>, TrkB, mTOR and AMPA receptor activation—as classic psychedelics and that TBG-induced cortical spinogenesis is required for the sustained antidepressant-like behavioral effect of TBG. In contrast to psychedelics, TBG does not induce an immediate glutamate burst or IEG activation. As these effects have been assumed to be necessary for psychedelic-induced neuroplasticity, our results shed light on the mechanisms by which certain psychoplastogens can promote cortical neuroplasticity in the absence of hallucinogenic effects.</p>

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The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation

  • 期刊论文

  • 发表日期：

    2025年8月4日

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  • Isak K. Aarrestad,
  • Lindsay P. Cameron,
  • Ethan M. Fenton,
  • Austen B. Casey,
  • Daniel R. Rijsketic,
  • Seona D. Patel,
  • Rohini Sambyal,
  • Shane B. Johnson,
  • Calvin Ly,
  • Jayashri Viswanathan,
  • Eden V. Barragan,
  • Stephanie A. Lozano,
  • Nicolas Seban,
  • Hongru Hu,
  • Noel A. Powell,
  • Milan Chytil,
  • Retsina Meyer,
  • David Rose,
  • Chris Hempel,
  • Eric Olson,
  • Hanne D. Hansen,
  • Clara A. Madsen,
  • Gitte M. Knudsen,
  • Chase Redd,
  • Damian G. Wheeler,
  • Nathaniel Guanzon,
  • Jessie Muir,
  • Joseph J. Hennessey,
  • Gerald Quon,
  • John D. McCorvy,
  • Sunil P. Gandhi,
  • Kurt Rasmussen,
  • Conor Liston,
  • John A. Gray,
  • Boris D. Heifets,
  • Alex S. Nord,
  • Christina K. Kim,
  • David E. Olson

摘要

Nonhallucinogenic psychoplastogens, such as tabernanthalog (TBG), are being developed as potentially safer, more scalable alternatives to psychedelics for promoting neuronal growth and treating various brain conditions. Currently, it is unclear whether 5-hydroxytryptamine 2A (5-HT2A) receptors and immediate early gene (IEG) activation have a role in the neuroplasticity-promoting effects of nonhallucinogenic psychoplastogens. Here, we use pharmacological and genetic tools in rodents to show that nonhallucinogenic psychoplastogens promote cortical neuroplasticity through the same biochemical pathway—involving 5-HT2A, TrkB, mTOR and AMPA receptor activation—as classic psychedelics and that TBG-induced cortical spinogenesis is required for the sustained antidepressant-like behavioral effect of TBG. In contrast to psychedelics, TBG does not induce an immediate glutamate burst or IEG activation. As these effects have been assumed to be necessary for psychedelic-induced neuroplasticity, our results shed light on the mechanisms by which certain psychoplastogens can promote cortical neuroplasticity in the absence of hallucinogenic effects.