eNeuroOct 27, 2025

Psychedelics Reverse the Direction of Long-Term Synaptic Changes in Claustrum Neurons That Connect to the Thinking Areas of the Brain

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 27, 2026

Abstract

Essence

The psychedelic DOI shifted claustrum-to-anterior-cingulate synapses in male rats from depression toward potentiation.

Evidence

This preclinical electrophysiology study paired presynaptic stimulation with postsynaptic action potentials in ACC-projecting claustrum neurons from male rats, with and without DOI exposure.

Caveat

The findings are limited to an acute rat brain-circuit preparation and do not show behavioral or therapeutic effects in psychiatric disease.

Simplified

Psychedelic drugs have garnered increasing attention for their therapeutic potential in treating a variety of psychiatric diseases, such as depression, anxiety, and substance use disorder. The claustrum (CLA), a brain area with remarkable interconnectivity to frontal cortices, has recently been shown to have a dense population of serotonin 2 receptors (5-HT2Rs) that are activated by psychedelics. Because psychedelic therapy can require as little as one treatment session, it has been speculated that psychedelics achieve their long-term remedial effects by inducing neuroplasticity in brain areas responsible for psychiatric disease states, such as the anterior cingulate cortex (ACC). However, the effects of psychedelics on in serotonin receptor-rich brain areas remain entirely unexplored. We applied presynaptic stimuli paired with postsynaptic action potentials (APs) to a subpopulation of CLA neurons projecting to ACC in male rats to find that the psychedelic drug, 2,5-dimethoxy-4-iodoamphetamine (DOI), reverses the polarity of synaptic plasticity from (LTD) to (LTP) in a manner that may reflect contribution of excitatory or inhibitory neurotransmission but is specific to synapses activated by local electrical stimulation. Additionally, we characterize intrinsic electrophysiological properties of CLA-ACC neurons with and without DOI application, noting several changes to AP dynamics induced by DOI. These findings align with the view that psychedelics induce rapid and lasting synaptic plasticity and strengthen the hypothesis that claustrocortical circuits are highly sensitive to psychedelic drug action.

Key numbers

5.580

Increase in synaptic efficacy

Cohen's d value for induction with application.

8.627

observed in control conditions

Cohen's d value for in without .

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Psychedelics Reverse the Direction of Long-Term Synaptic Changes in Claustrum Neurons That Connect to the Thinking Areas of the Brain

Abstract

Key numbers

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