The psychoplastogen tabernanthalog induces neuroplasticity without proximate immediate early gene activation
Aarrestad, I. K., Barragan, E. V., Cameron, L. P., Casey, A. B., Chytil, M., Fenton, E. M., Ghandi, S. P., Gray, J. A., Guanzon, N., Hansen, H. D., Heifets, B. D., Hempel, C., Hennesssey, J. J., Hu, H., Johnson, S. B., Kim, C. K., Knudsen, G. M., Liston, C., Lozano, S. A., Ly, C., Madsen, C. A., McCorvy, J. D., Meyer, R., Muir, J., Nord, A. S., Olson, D. E., Olson, E., Patel, S. D., Powell, N. A., Quon, G., Rasmussen, K., Redd, C., Rijsketic, D. R., Rose, D., Sambyal, R., Seban, N., Viswanathan, J., Wheeler, D. G.
This rodent study found that the nonhallucinogenic psychoplastogen tabernanthalog (TBG) promotes cortical neuroplasticity and sustained antidepressant effects through the same 5-HT2A, TrkB, mTOR, and AMPA receptor pathway as psychedelics, but without inducing the immediate glutamate burst or immediate early gene activation previously thought necessary for psychedelic-induced neuroplasticity.
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-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.