Serotonin and psilocybin activate 5-HT1B receptors to suppress cortical signaling through the claustrum
Maxwell B. Madden, Chloe Schaefgen, Binita Vedak, J.s. Kwon, Kiara S. Dresp Pedra, Samuel H. Sheats, Adam C. Puché, Steffen B. E. Wolff, Brian N. Mathur
Nature Communications August 19, 2025 DOI: 10.1038/s41467-025-62980-8 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Interventions | serotonin psilocybin |
| Topics | Psilocybin Serotonin |
| Keywords | Claustrum Hallucinogen 5-HT Receptor |
| Citations | 4 |
| Key findings | Serotonin and psilocybin both activate 5-HT1B receptors on anterior cingulate cortex inputs to suppress signaling through the claustrum to parietal association cortex-projecting neurons. |
Abstract
Through its widespread reciprocal connections with the cerebral cortex, the claustrum is implicated in sleep and waking cortical network states. Yet, basic knowledge of neuromodulation in this structure is lacking. The claustrum is richly innervated by serotonergic fibers, expresses serotonin receptors, and is suggested to play a role in the ability of psilocybin, which is metabolized to the non-specific serotonin receptor agonist psilocin, to disrupt cortex-wide network states. We therefore addressed the possible role of serotonin, and the classic psychedelic psilocybin, in modulating cortical signaling through the claustrum. We show that serotonin activates 5-HT1B receptors on anterior cingulate cortex inputs - a primary driver of claustrum activity - to suppress signaling to parietal association cortex-projecting claustrum neurons. Additionally, we demonstrate that psilocybin injection also activates anterior cingulate cortex presynaptic 5-HT1B receptors to suppress cortical signaling through the claustrum. Thus, serotonin, via 5-HT1B, may provide gain-control of cortical input to the claustrum, a mechanism that may be directly targeted by psilocybin to modulate downstream cortical network states.
Comparable studies
Other experimental studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers | 1998 | Experimental study | |
| Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | 2000 | Experimental study | |
| Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Rat brain | 1988 | Experimental study | |
| The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Human platelet plasma membrane vesicles and bovine adrenal chromaffin granule membrane... | 1992 | Laboratory study | |
| 5-HT2AReceptor-Mediated Regulation of Brain-Derived Neurotrophic Factor mRNA in the Hippocampus and the Neocortex Rat brain | 1997 | Experimental study |
Citations in the library
Cited by 2
- Psychedelics and the Extracellular Matrix: Rewiring Neuroplasticity and Metaplasticity for Next-Generation Psychiatric Therapies Biological Psychiatry February 1, 2026
- The serotonin 1B receptor as a target for the treatment of depression and anxiety Expert Opinion on Therapeutic Targets September 21, 2026
Cites 16
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
- Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Proceedings of the National Academy of Sciences April 13, 2021
- Psilocybin desynchronizes the human brain. Nature August 1, 2024
- Htr2a gene and 5-HT2A receptor expression in the cerebral cortex studied using genetically modified mice Frontiers in Neuroscience 2010
- Models of psychedelic drug action: modulation of cortical-subcortical circuits Brain October 22, 2021
and 11 more in the library