Psychedelics reopen the social reward learning critical period
This mice study shows that psychedelics (including ketamine & MDMA) open a social reward learning critical period. The duration of the drugs' effects in humans is proportional to the time it takes for the critical period to reopen. Additionally, the restoration of oxytocin-mediated long-term depression in the nucleus accumbens is associated with the reinstatement of social reward learning in adulthood. The study also found that reorganising the extracellular matrix is a common mechanism underlying the critical period reopening caused by psychedelic drugs.
Authors
- Nardou, R.
- Sawyer, E.
- Song, Y. J.
Published
Abstract
Psychedelics are a broad class of drugs defined by their ability to induce an altered state of consciousness. These drugs have been used for millennia in both spiritual and medicinal contexts, and a number of recent clinical successes have spurred a renewed interest in developing psychedelic therapies. Nevertheless, a unifying mechanism that can account for these shared phenomenological and therapeutic properties remains unknown. Here we demonstrate in mice that the ability to reopen the social reward learning critical period is a shared property across psychedelic drugs. Notably, the time course of critical period reopening is proportional to the duration of acute subjective effects reported in humans. Furthermore, the ability to reinstate social reward learning in adulthood is paralleled by metaplastic restoration of oxytocin-mediated long-term depression in the nucleus accumbens. Finally, identification of differentially expressed genes in the ‘open state’ versus the ‘closed state’ provides evidence that reorganization of the extracellular matrix is a common downstream mechanism underlying psychedelic drug-mediated critical period reopening. Together these results have important implications for the implementation of psychedelics in clinical practice, as well as the design of novel compounds for the treatment of neuropsychiatric disease.
Research Summary of 'Psychedelics reopen the social reward learning critical period'
Introduction
Despite several decades of renewed clinical interest in psychedelic therapy and accumulating evidence of efficacy across conditions including depression, PTSD, and addiction, the neurobiological mechanism through which diverse psychedelic compounds — with distinct primary binding targets and signalling profiles — produce shared and durable therapeutic effects has remained unknown. Critical periods are developmental windows during which the nervous system exhibits heightened plasticity in response to specific experiential inputs; their closure in early adulthood is thought to underlie the relative rigidity of established perceptual and behavioural patterns. Prior work demonstrated that MDMA reopens a critical period for social reward learning in adult mice, reinstating the capacity for social conditioned place preference that normally closes with neurological maturation. The present study tested whether critical period reopening represents a shared property across pharmacologically diverse psychedelic compounds, investigated the time course of the resulting open state in relation to human subjective effect duration, characterised the synaptic mechanism underlying reinstatement of social reward learning, and identified the molecular and genomic signature of the open state through transcriptomic analysis of the nucleus accumbens.
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Study Details
- Study Typeindividual
- Journal
- Compounds
- Topics
- APA Citation
Nardou, R., Sawyer, E., Song, Y. J., Wilkinson, M., Padovan-Hernandez, Y., de Deus, J. L., Wright, N., Lama, C., Faltin, S., Goff, L. A., Stein-O’Brien, G. L., & Dölen, G. (2023). Psychedelics reopen the social reward learning critical period. Nature, 618(7966), 790-798. https://doi.org/10.1038/s41586-023-06204-3
References (22)
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Frampton, C. M., Yazar-Klosinski, B., Nollar, G. E. · The American Journal of Drug and Alcohol Abuse (2017)
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Mitchell, J., Bogenschutz, M. P., Lilienstein, A. et al. · Nature Medicine (2021)
Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T. et al. · Journal of Psychopharmacology (2012)
Carhart-Harris, R. L., Giribaldi, B., Watts, R. et al. · New England Journal of Medicine (2021)
Nardou, R., Lewis, E. M., Rothhaas, R. et al. · Nature (2019)
Bedi, G., Hyman, D., De Wit, H. · Biological Psychiatry (2010)
Holze, F., Vizeli, P., Müller, F. et al. · Neuropsychopharmacology (2019)
Halberstadt, A. L., Chatha, M., Klein, A. K. et al. · Neuropharmacology (2020)
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Show all 22 referencesShow fewer
Schmid, Y., Enzler, F., Gasser, P. et al. · Biological Psychiatry (2015)
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Hesselgrave, N., Troppoli, T. A., Wulff, A. B. et al. · PNAS (2021)
Vargas, M. V., Dunlap, L. E., Dong, C. et al. · Science (2023)
Young, M. B., Norrholm, S. D., Khoury, L. M. et al. · Psychopharmacology (2017)
Flanagan, T. W., Nichols, C. D. · International Review of Psychiatry (2018)
Ly, C., Greb, A. C., Cameron, L. P. et al. · Cell Reports (2018)
Shao, L-X,, Liao, C., Gregg, I. et al. · Neuron (2021)
Kuypers, K. P. C., Riba, &. J., De La Fuente Revenga, &. M. et al. · Psychopharmacology (2016)
Davis, A. K., Barrett, F. S., Griffiths, R. R. · Journal of Contextual Behavioral Science (2020)
Agin-Liebes, G. I., Zeifman, R. J., Luoma, J. B. et al. · Journal of Psychopharmacology (2022)
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