Psychedelics reopen the social reward learning critical period

• Published in: Nature (London) 2023-06, Vol.618 (7966), p.790-798
• Main Authors: Nardou, Romain, Sawyer, Edward, Song, Young Jun, Wilkinson, Makenzie, Padovan-Hernandez, Yasmin, de Deus, Júnia Lara, Wright, Noelle, Lama, Carine, Faltin, Sehr, Goff, Loyal A., Stein-O’Brien, Genevieve L., Dölen, Gül
• Format: Article
• Language: English
• Subjects: 38; 38/91; 631/378/1595/2167; 631/378/2645/2646; 631/378/3919; 64; 64/60; 82; 9/74; Animals; Cocaine; Consciousness - drug effects; Critical period; Critical Period, Psychological; Drug dosages; Drugs; Ecstasy; Extracellular matrix; Extracellular Matrix - drug effects; Hallucinogens - pharmacology; Hallucinogens - therapeutic use; Hormones; Humanities and Social Sciences; Humans; Learning; Learning - drug effects; Long-term depression; Long-Term Synaptic Depression - drug effects; LSD; Lysergic acid diethylamide; Mental disorders; Mice; multidisciplinary; Nucleus accumbens; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Oxytocin; Oxytocin - metabolism; Psychedelic drugs; Reinforcement; Reward; Science; Science (multidisciplinary); Social discrimination learning; Time Factors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-023-06204-3

Psychedelics are a broad class of drugs defined by their ability to induce an altered state of consciousness 1 , 2 . 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 3 – 9 . 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. Behavioural electrophysiological and transcriptomic studies in mice show that psychedelic drugs reopen the social reward learning critical period and suggest that this involves reorganization of the extracellular matrix.