Compound-Induced Neuroplasticity Without Immediate Early Gene Activation

Cortical atrophy and dysfunction are hallmarks of many neuropsychiatric diseases including depression, post-traumatic stress disorder (PTSD), and addiction. Psychoplastogens are small molecules with the potential to rapidly rescue these structural and functional deficits, leading to sustained therapeutic effects after a single administration. Classic psychedelics are among the most potent and efficacious psychoplastogens known, with recent data indicating that their clinical and preclinical effects might be more robust and durable than those of ketamine. Moreover, the advent of non-hallucinogenic psychoplastogens structurally related to psychedelics, such as tabernanthalog (TBG), has opened new opportunities for developing scalable alternatives capable of promoting structural and functional neuroplasticity in the prefrontal cortex (PFC). Currently, it is unclear what roles 5-HT2A receptors (5-HT2ARs) and immediate early gene activation play in the neuroplasticity-promoting effects of non-hallucinogenic psychoplastogens like TBG—information necessary to engineer optimized neurotherapeutics related to psychedelics. Here, we use a combination of pharmacological and genetic tools to demonstrate that several non-hallucinogenic psychoplastogens promote cortical neuron growth through the same biochemical pathway as classic psychedelics. Furthermore, we demonstrate that there is a causal relationship between TBG-induced cortical spinogenesis and its sustained antidepressant-like effects. In contrast to psychedelics, TBG promotes cortical neuron growth in the absence of a glutamate burst or immediate early gene (IEG) activation, effects assumed to be necessary for psychedelic-induced neuroplasticity. Our results elucidate how the hallucinogenic effects of psychedelics can be decoupled from their beneficial effects on cortical neuron growth. Mice were treated with i.p. drug (5-MeO-DMT, TBG, or VEH) and Prefrontal Cortex (PFC) was dissected 1 hour later and analyzed with snRNAseq.