Prolonged epigenetic and synaptic plasticity alterations following single exposure to a psychedelic in mice
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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.
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Ketamine and psychedelics modulate cortical neuron function by increasing dendritic spine and synapse density in the PFC.
“Ketamine and psychedelics modulate cortical neuron function by increasing dendritic spine and synapse density in the PFC (129, 146–149)”
From Psychedelics and Other Psychoplastogens for Treating Mental Illness. (2021) · cites this paper as [149]
In “Psychedelics enhance cortical dendritic density via 5-HT2AR” (page unavailable), the paper reports that DOI increased thin and stubby dendritic spine density in frontal-cortex neurons of adult mice and enhanced synaptic plasticity. It does not report a ketamine experiment or directly establish an increase in synapse density, so those parts of the attributed claim are not supported by this paper. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe same DOI treatment evoked chromatin changes that persisted long after the DOI treatment.
“The same treatment evoked chromatin changes that persisted long after the DOI treatment”
From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [109]
A single dose of DOI exerted rapid effects on dendritic spine structure in frontal cortex that were dependent on 5HT2A receptors.
“In a recent rodent study, a single dose of DOI exerted rapid effects on the dendritic spine structure in frontal cortex that were dependent on 5HT2A receptors [109].”
From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [109]
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Beyond the 5-HT2AReceptor: Classic and Nonclassic Targets in Psychedelic Drug Action
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Psychedelics and Neural Plasticity: Therapeutic Implications
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Serotonergic Psychedelics in Neural Plasticity
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LSD induces increased signalling entropy in rats’ prefrontal cortexPreprint
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- Authors
- de la Fuente Revenga, M., Zhu, B., Guevara, C. A., Naler, L. B., Saunders, J. M., Zhou, Z., Toneatti, R., Sierra, S., Wolstenholme, J. T., Beardsley, P. M., Huntley, G. W., Lu, C., & González-Maeso, J.
- Affiliations
- Virginia Tech (US)
- Icahn School of Medicine at Mount Sinai (US)
- Virginia Commonwealth University (US)
- Corresponding author
- Lu, Chang
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2021-02-25
- OpenAlex
- W3131550087
- Cited by
- 11
- References
- 87
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 6
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- National Institutes of Health (N01DA-17-8932, NIH-N01DA-17-8932, N01DA-19-8949, NIH-N01DA-19-8949)
- National Institute on Alcohol Abuse and Alcoholism (P50AA022537)
- National Institute of Mental Health (R01MH111940, R01MH084894, T32MH020030, T32MH087004)
- National Institute on Drug Abuse (P30DA033934)
- National Institute of Biomedical Imaging and Bioengineering (R01EB017235)
- Topics
- Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- psychedelics, digital object identifiers, 2C-B, epigenetic modifications, chromatin organization, synaptic plasticity, dendritic spines, fear extinction, 5-HT2A receptor, frontal cortex, schizophrenia risk, psychosis, depression
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