Prolonged epigenetic and synaptic plasticity alterations following single exposure to a psychedelic in mice
OpenAlex – February 25, 2021
Source: OpenAlex
Summary
A single dose of a psychedelic drug rapidly improved mood by accelerating fear extinction through specific neurotransmitter receptor influence, impacting systems linked to tryptophan. Neuroscience reveals this antidepressant effect stems from epigenetic changes: the drug alters chromatin organization and the epigenome, particularly impacting synaptic plasticity for days. These biological shifts, relevant to Psychology and Drug Studies, overlap with genetic markers for schizophrenia and other psychosis risks. This suggests epigenetic-driven synaptic changes are key, but warrants caution for individuals with such predispositions.
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.