Psychedelic drug action at dendrites is gated by behavioral state and serotonin receptors
Neil K. Savalia, Ling-Xiao Shao, Cory A. Knox, Annie-Kim Gilbert, Quan Jiang, Alex C. Kwan
bioRxiv (Cold Spring Harbor Laboratory) July 20, 2026 preprint DOI: 10.64898/2026.07.16.738983 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Mouse medial frontal cortex pyramidal tract neurons |
| Intervention | Psilocybin |
| Topics | Neuroplasticity Psilocybin Serotonin |
| Keywords | Dendritic spine Dendritic filopodia Hallucinogen Pyramidal cell Dendrite mathematics Long-term potentiation Solitary tract Receptor Dendritic spike Calcium signaling Calcium imaging Drug action Calbindin |
| Key findings | Psilocybin transiently increases dendritic calcium event rates in apical tufts in a brain state- and 5-HT2A receptor-dependent manner, and alters the predictive relationship between acute dendritic calcium signaling and subsequent spine formation. |
Abstract
SUMMARY How psychedelics act on cortical dendrites to produce long-lasting structural plasticity remains poorly understood. Here, we characterize the effects of psilocybin on dendritic calcium dynamics in pyramidal tract neurons of the mouse medial frontal cortex. Psilocybin transiently increases calcium event rates in apical dendritic tufts over a time course that parallels the drug’s pharmacokinetics in the brain. This acute effect is brain state-dependent, occurring selectively during quiet wakefulness, and was abolished by cell type-specific deletion of the 5-HT 2A receptor. Under control conditions, dendritic calcium signaling predicts subsequent spine formation, but this relationship is not preserved following psilocybin administration. Together, these findings reveal that psilocybin engages brain state- and 5-HT 2A receptor-dependent dendritic signaling, while altering the relationship between acute dendritic activity and long-term structural plasticity. The results suggest that the mechanisms linking acute dendritic signaling to structural remodeling differ between physiological and psychedelic-induced plasticity.
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 |