Aarrestad Isak K, Cameron Lindsay P, Fenton Ethan M, Casey Austen B, Rijsketic Daniel R, Patel Seona D, Sambyal Rohini, Johnson Shane B, Ly Calvin, Viswanathan Jayashri, Barragan Eden V, Lozano Stephanie A, Seban Nicolas, Hu Hongru, Powell Noel A, Chytil Milan, Meyer Retsina, Rose David, Hempel Chris, Olson Eric, Hansen Hanne D, Madsen Clara A, Knudsen Gitte M, Redd Chase, Wheeler Damian G, Guanzon Nathaniel, Muir Jessie, Hennessey Joseph J, Quon Gerald, McCorvy John D, Gandhi Sunil P, Rasmussen Kurt, Liston Conor, Gray John A, Heifets Boris D, Nord Alex S, Kim Christina K, Olson David E
Neuroscience Graduate Program, University of California, Davis, Davis, CA, USA.
Institute for Psychedelics and Neurotherapeutics, University of California, Davis, Davis, CA, USA.
Nat Neurosci. 2025 Aug 4. doi: 10.1038/s41593-025-02021-1.
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) 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, 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.
非致幻性精神可塑性药物，如他贝宁（TBG），正被开发为潜在更安全、更具可扩展性的替代致幻剂，用于促进神经元生长和治疗各种脑部疾病。目前，尚不清楚5-羟色胺2A（5-HT）受体和即刻早期基因（IEG）激活在非致幻性精神可塑性药物促进神经可塑性的作用中是否发挥作用。在此，我们在啮齿动物中使用药理学和遗传学工具表明，非致幻性精神可塑性药物通过与经典致幻剂相同的生化途径促进皮质神经可塑性，该途径涉及5-HT、TrkB、mTOR和AMPA受体激活，并且TBG诱导的皮质树突棘生成是TBG持续抗抑郁样行为效应所必需的。与致幻剂不同，TBG不会诱导立即的谷氨酸爆发或IEG激活。由于这些效应被认为是致幻剂诱导神经可塑性所必需的，我们的结果揭示了某些精神可塑性药物在无致幻作用的情况下促进皮质神经可塑性的机制。
