Distinct 5-HT receptor subtypes regulate claustrum excitability by serotonin and the psychedelic, DOI
Tanner L. Anderson, Jack V. Keady, Judy Songrady, Navid S. Tavakoli, Artin Asadipooya, Ryson E. Neeley, Jill R. Turner, Pavel I. Ortinski
Progress in Neurobiology August 1, 2024 DOI: 10.1016/j.pneurobio.2024.102660 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical electrophysiological study Peer reviewed |
|---|---|
| Population | Claustrum neurons projecting to the anterior cingulate cortex |
| Interventions | DOI 5-HT |
| Topics | Serotonin |
| Key points | Serotonin and the psychedelic DOI had opposite effects on excitatory synaptic currents in claustrum neurons projecting to the anterior cingulate cortex: serotonin inhibited these currents while DOI stimulated them. Both effects were reversed by blocking 5-HT2C receptors, but not 5-HT2A receptors, leading the authors to argue against the canonical role of 5-HT2A in this circuit. |
Abstract
Recent evidence indicates that neuronal activity within the claustrum (CLA) may be central to cellular and behavioral responses to psychedelic hallucinogens. The CLA prominently innervates many cortical targets and displays exceptionally high levels of serotonin (5-HT) binding. However, the influence of serotonin receptors, prime targets of psychedelic drug action, on CLA activity remains unexplored. We characterize the CLA expression of all known 5-HT subtypes and contrast the effects of 5-HT and the psychedelic hallucinogen, 2,5-dimethoxy-4-iodoamphetamine (DOI), on excitability of cortical-projecting CLA neurons. We find that the CLA is particularly enriched with 5-HT2C receptors, expressed predominantly on glutamatergic neurons. Electrophysiological recordings from CLA neurons that project to the anterior cingulate cortex (ACC) indicate that application of 5-HT inhibits glutamate receptor-mediated excitatory postsynaptic currents (EPSCs). In contrast, application of DOI stimulates EPSCs. We find that the opposite effects of 5-HT and DOI on synaptic signaling can both be reversed by inhibition of the 5-HT2C, but not 5-HT2A, receptors. We identify specific 5-HT receptor subtypes as serotonergic regulators of the CLA excitability and argue against the canonical role of 5-HT2A in glutamatergic synapse response to psychedelics within the CLA-ACC circuit.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 5
- Psychedelic Drugs in Mental Disorders: Current Clinical Scope and Deep Learning‐Based Advanced Perspectives Advanced Science March 20, 2025
- Serotonin and psilocybin activate 5-HT1B receptors to suppress cortical signaling through the claustrum Nature Communications August 19, 2025
- Psychedelics Reverse the Polarity of Long-Term Synaptic Plasticity in Cortical-Projecting Claustrum Neurons eNeuro October 1, 2025
- MDMA enhances prefrontal plasticity and representational drift during fear extinction bioRxiv (Cold Spring Harbor Laboratory) March 8, 2026
- Effective connectivity of the human claustrum: Triple networks, subcortical circuits, and psychedelic modulation bioRxiv (Cold Spring Harbor Laboratory) September 12, 2025
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and 34 more in the library