Prolonged epigenetic and synaptic plasticity alterations following single exposure to a psychedelic in mice
Mario de la Fuente Revenga, Bohan Zhu, Christopher A. Guevara, Lynette B. Naler, Justin M. Saunders, Zirui Zhou, Rudy Toneatti, Salvador Sierra, Jennifer T Wolstenholme, Patrick M. Beardsley, George W. Huntley, Chang Lu, Javier González-Maeso
bioRxiv (Cold Spring Harbor Laboratory) February 25, 2021 preprint DOI: 10.1101/2021.02.24.432725 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Mice |
| Intervention | DOI |
| Dose | single dose |
| Topics | Neuroplasticity |
| Keywords | Antidepressant Epigenetics Psychosis Schizophrenia object-oriented programming Chromatin Epigenome Extinction optical mineralogy Receptor Hippocampus Dna methylation |
| Citations | 11 |
| Key findings | A single dose of DOI induces lasting changes in chromatin organization at enhancer regions of synaptic assembly genes via the 5-HT2A receptor, driving synaptic plasticity and fear extinction, which may explain its rapid antidepressant action, while also overlapping with genetic risk loci for psychiatric disorders. |
Abstract
Clinical evidence suggests a potential therapeutic effect of classic psychedelics for the treatment of depression. The most outstanding and distinct characteristic is the rapid and sustained antidepressant action with one single exposure to the drug. However, the biological substrates and key mediators of psychedelics’ enduring action remain unknown. Here, we show that a single administration of the psychedelic DOI produced fast-acting effects on frontal cortex dendritic spine structure and acceleration of fear extinction via the 5-HT 2A receptor. Additionally, a single dose of DOI led to changes in chromatin organization particularly at enhancer regions of genes involved in synaptic assembly that stretched for days after the psychedelic exposure. DOI-induced alterations in neuronal epigenome overlapped with genetic loci associated with schizophrenia, depression and attention deficit hyperactivity disorder. Together, these data support the notion that epigenetic-driven changes in synaptic plasticity operate as the mechanistic substrate of psychedelic’s long-lasting antidepressant action but also warn on the limitations in individuals with underlying risk for psychosis.
Comparable studies
Other preclinical and animal studies on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Mice | 2023 | Experimental study | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study | |
| The alkaloids of Banisteriopsis caapi, the plant source of the Amazonian hallucinogen Ayahuasca, stimulate adult neurogenesis in vitro Progenitor cells from subventricular and subgranular zones of adult mice brains | 2017 | In vitro experimental study | |
| N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo Mice | 2020 | In vitro and in vivo experimental study |
Citations in the library
Cited by 10
- Psychedelics and Other Psychoplastogens for Treating Mental Illness Frontiers in Psychiatry October 4, 2021
- Classic Psychedelic Drugs: Update on Biological Mechanisms Pharmacopsychiatry January 25, 2022
- Beyond the 5-HT2A Receptor: Classic and Nonclassic Targets in Psychedelic Drug Action. Journal of Neuroscience November 8, 2023
- Psychedelic Therapy's Transdiagnostic Effects: A Research Domain Criteria (RDoC) Perspective Frontiers in Psychiatry December 17, 2021
- Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans Molecules April 22, 2021
and 5 more in the library
Cites 26
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Synaptic Dysfunction in Depression: Potential Therapeutic Targets Science October 4, 2012
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
and 21 more in the library