Psychedelics Reverse the Polarity of Long-Term Synaptic Plasticity in Cortical-Projecting Claustrum Neurons
Tanner L. Anderson, Artin Asadipooya, Pavel I. Ortinski
eNeuro October 1, 2025 Peer reviewed DOI: 10.1523/eneuro.0047-25.2025 via OpenAlex
Summary
The psychedelic drug 2,5-dimethoxy-4-iodoamphetamine (DOI) was found to reverse synaptic plasticity from long-term depression to long-term potentiation in claustrum neurons projecting to the anterior cingulate cortex in male rats. This change may involve both excitatory and inhibitory neurotransmission and is specific to synapses activated by local electrical stimulation. The study highlights that psychedelics can induce significant changes in synaptic dynamics, supporting the idea of their role in promoting neuroplasticity related to psychiatric disorders.
Study at a glance
| Population | male rats |
|---|---|
| Key finding | DOI reverses the polarity of synaptic plasticity from long-term depression to long-term potentiation in claustrum neurons. |
Abstract
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 synaptic plasticity 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 long-term depression (LTD) to long-term potentiation (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.