Elucidating the neurocircuitry behind behaviors evoked by the serotonergic psychedelic DOI

Abstract

Serotonergic psychedelics are psychoactive substances with the capacity to alter one’s perception and mood via their action on the serotonin 5HT2A receptor. Recent studies have identified their potential as fast-acting therapeutics to a range of psychiatric conditions including Major Depressive Disorder (MDD), anxiety and Post Traumatic Stress Disorder (PTSD). While clinical studies are exploring the range of effects wielded by psychedelics, there are still gaps in our understanding of how they modulate behavioral changes at the level of neural circuits and networks. A significant acute effect of psychedelics is their ability to induce intense visual and auditory hallucinations in humans. In the case of psychedelic-assisted psychotherapy, it is unclear whether these subjective hallucinatory effects are important for the therapeutic benefits of psychedelics. In order to parcellate the neural underpinnings of these acute behavioral effects, we sought to study psychedelic-induced behaviors in rodents, namely the Head Twitch Response (HTR) and the Ear Scratch Response (ESR). These are behaviors considered to be the best available ‘proxy’ for the serotonin 2A receptor activation as well as hallucinatory responses. This is primarily due to the high positive correlation between the potency of psychedelics to cause HTRs in rodents and their potency to cause hallucinations in humans. Through different genetic and surgical manipulations, we aimed to identify the role of the serotonin 5HT2AR in modulating HTRs and ESRs across cell types and brain regions. Our studies reveal that the HTR and ESR are 5HT2AR mediated behaviors with sex-, strain- and species-specific differences. Among excitatory and inhibitory neural cell types, we identified that the 5HT2A receptor on the CaMKII and SST positive cells regulate HTRs. While the PFC has been implicated strongly in mediating psychedelic-induced cellular and behavioral effects, we find that the activation of the mPFC 5HT2AR is not sufficient to evoke HTRs or ESRs in mice and rats. Further study of other brain regions implicated in motor output, such as the Motor Cortex and the Striatum, also revealed that selective activation of the 5HT2A receptor in these regions was not sufficient to induce HTRs. Considering the immense therapeutic potential of psychedelics, we aimed to identify the role of the 5HT2AR in mediating anxiolysis and antidepressive behavior. Through behavioral analysis on the Forced Swim Test and Elevated Plus Maze assays, it was revealed that systemic DOI injection led to significant anxiolysis in a 5HT2A receptor dependent manner. A similar effect was not observed in the case of anti-depressive behavior. Taken together, these results provide key insights into the neural regulation of acute behavioral effects of psychedelics.