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Psychedelics reopen the social reward learning critical period

Medicine and Health

Psychedelics reopen the social reward learning critical period

R. Nardou, E. Sawyer, et al.

This groundbreaking study reveals that psychedelic drugs can reopen the social reward learning critical period in mice, with effects tied to subjective experiences seen in humans. The research, conducted by notable authors at Johns Hopkins University, uncovers crucial mechanisms that could advance psychedelic therapies for neuropsychiatric conditions.

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Playback language: English
Introduction
Psychedelics, a diverse class of drugs inducing altered states of consciousness, have shown therapeutic promise in treating various conditions like addiction, PTSD, and depression. However, a unifying mechanism explaining their shared effects remains elusive. Previous research revealed that the empathogenic psychedelic MDMA reopens a critical period for social reward learning, a finding linked to MDMA's therapeutic effects. This study investigates whether this critical period reopening generalizes across different classes of psychedelics, regardless of their subjective effects (hallucinogenic, empathogenic, dissociative, or oneirogenic), chemical structures, or primary binding targets.
Literature Review
The literature on psychedelics is extensive, encompassing their historical uses and recent clinical trials. While various classification schemes exist (based on subjective effects, chemical structure, or binding targets), their relevance to therapeutic applications is unclear. The shared therapeutic potential of diverse psychedelics highlights the need for identifying a common neurobiological mechanism. The concept of critical periods in brain development, characterized by heightened sensitivity to stimuli and increased plasticity, has gained attention. The ability to reopen these periods holds therapeutic potential. Previous work demonstrated that MDMA reopens the social reward learning critical period, and this mechanism shares features with its therapeutic effects in PTSD treatment. However, the generalizability of this effect across psychedelics was unknown.
Methodology
The study used a social reward conditioned place preference (sCPP) assay in adult male mice. Various psychedelics (psilocybin, LSD, ketamine, ibogaine) were administered intraperitoneally, followed by an assessment of sCPP 48 hours later. A natural spline regression model was used to define 'open' and 'closed' states of the critical period. The duration of the open state was investigated by assessing sCPP at multiple time points after psychedelic treatment. Ex vivo electrophysiological recordings from medium spiny neurons (MSNs) in the nucleus accumbens (NAc) were performed to examine the effects of psychedelics on oxytocin-mediated long-term depression. RNA sequencing of the NAc was conducted to identify differentially expressed genes in the 'open' versus 'closed' states. Experiments also investigated the role of the 5-HT2AR receptor and β-arrestin-2 signaling in critical period reopening. Control groups received saline or cocaine.
Key Findings
The study found that all tested psychedelics reopened the social reward learning critical period in adult mice. The duration of this 'open state' varied across psychedelics, correlating with the duration of acute subjective effects in humans. Ketamine's effects were short-lived (1 week), psilocybin's lasted 2 weeks, LSD's 3 weeks, and ibogaine's at least 4 weeks. Electrophysiological recordings showed that psychedelics induced metaplastic upregulation of oxytocin-mediated long-term depression in the NAc, a mechanism not observed with cocaine. RNA sequencing revealed that the shared ability to reopen the critical period converged on transcriptional regulation of the extracellular matrix (ECM), with changes in genes related to ECM remodeling. While 5-HT2AR receptors were involved in LSD and psilocybin's effects, MDMA and ketamine acted independently of this receptor. Similarly, β-arrestin-2 signaling was necessary for LSD and MDMA but not for ketamine and ibogaine.
Discussion
The findings provide a unifying neurobiological mechanism for the diverse therapeutic effects of psychedelics: the reopening of critical periods. The duration of the open state, correlated with the duration of subjective effects in humans, explains the variable durations of therapeutic responses. The identification of ECM remodeling as a common downstream mechanism suggests a novel therapeutic target. The study distinguishes psychedelics from addictive drugs, as the former induce metaplasticity rather than hyperplasticity. The results support the use of the established naming convention for psychedelics, rather than sub-classification based on receptor binding or subjective properties. The shared molecular mechanism suggests psychedelics may act as a ‘master key’ for unlocking a broad range of critical periods, opening avenues for treating a wider range of neuropsychiatric disorders.
Conclusion
This research presents a novel framework for understanding the therapeutic effects of psychedelics, highlighting their capacity to reopen critical periods for social reward learning. The findings reveal a shared mechanism involving metaplasticity and extracellular matrix remodeling, explaining their therapeutic potential across diverse neuropsychiatric disorders. Future research should explore the potential of psychedelics to treat other conditions involving critical periods, such as autism and stroke.
Limitations
The study was conducted in mice, limiting the direct generalizability to humans. The focus on social reward learning may not fully capture the complexity of psychedelic effects on other brain functions and behaviors. While the study examined several psychedelics, other compounds within this diverse class require further investigation. Further research is needed to confirm the identified mechanisms in humans and to understand fully the clinical implications of these findings.
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