Faculty Collaboration Database

The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation. Nat Neurosci 2025 Sep;28(9):1919-1931

Date

08/05/2025

Pubmed ID

40760185

Pubmed Central ID

PMC12373294

DOI

10.1038/s41593-025-02021-1

Scopus ID

2-s2.0-105012563199 (requires institutional sign-in at Scopus site)   24 Citations

Abstract

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_2A) 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_2A, 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.

Author List

Aarrestad IK, Cameron LP, Fenton EM, Casey AB, Rijsketic DR, Patel SD, Sambyal R, Johnson SB, Ly C, Viswanathan J, Barragan EV, Lozano SA, Seban N, Hu H, Powell NA, Chytil M, Meyer R, Rose D, Hempel C, Olson E, Hansen HD, Madsen CA, Knudsen GM, Redd C, Wheeler DG, Guanzon N, Muir J, Hennessey JJ, Quon G, McCorvy JD, Gandhi SP, Rasmussen K, Liston C, Gray JA, Heifets BD, Nord AS, Kim CK, Olson DE

Author

John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Genes, Immediate-Early
Hallucinogens
Male
Mice
Mice, Inbred C57BL
Neuronal Plasticity
Rats
Receptor, Serotonin, 5-HT2A
Receptor, trkB
Receptors, AMPA
TOR Serine-Threonine Kinases