Contribution of the Serotonin 5-HT2A Receptor to the Therapeutic Effect of Psilocin on Social Behavior Deficits in Mice Repeatedly Exposed to Social Defeat Stress.
Daisuke Ibi, Rika Takaba, Keisuke Yoshida, Ririna Kawase, Hiroko Kitagawa, Momoko Matsushita, Kana Ito, Shoya Uno, Fumiya Nishimura, Shinji Kitagaki, Masayuki Hiramatsu
Neuropsychopharmacology Reports September 1, 2026 DOI: 10.1002/npr2.70152 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Mice subjected to chronic social defeat stress |
| Intervention | Psilocin |
| Topics | Psilocybin Serotonin |
| Keywords | Animals Mice, inbred c57bl Receptor, serotonin, 5-ht2a Hallucinogens Behavior, animal Stress, psychological Social behavior Male Social defeat stress Serotonin 5‐ht2a receptor |
| Key points | Psilocin administered after chronic social defeat stress ameliorated social avoidance behavior in mice, while administration before stress had little effect. The therapeutic effect was blocked by a 5-HT2A receptor antagonist, indicating it works through 5-HT2A receptor activation. The authors suggest psilocin may promote stress resilience rather than resistance. |
Abstract
Psychedelics such as psilocybin and lysergic acid diethylamide (LSD) exert hallucinogenic effects through stimulation of serotonin 5-HT2A receptors (5-HT2ARs) in the cerebral cortex. In recent years, numerous reports have demonstrated that psychedelics are effective in treating various psychiatric disorders such as major depressive disorder (MDD), treatment-resistant depression (TRD), and anxiety-related disorders. We have previously reported that administration of psilocin, the active metabolite of psilocybin, produces antidepressant-like effects in mice. Furthermore, we found that this effect is mediated by 5-HT2AR activation. Since depression and other psychiatric disorders often lead to impairments in social behavior (e.g., social avoidance), the present study examined the effects of psilocin on social avoidance behavior in mice subjected to chronic social defeat stress (CSDS), a widely used model that closely models human psychosocial stress. Mice exposed to CSDS exhibited social avoidance behavior, whereas psilocin administration before the onset of CSDS had little effect on this behavior. In contrast, psilocin administration after the completion of CSDS ameliorated social avoidance in CSDS-exposed mice. This effect was blocked by pretreatment with a 5-HT2AR antagonist, indicating that psilocin exerts its therapeutic effects through 5-HT2AR activation. Taken together, psilocin exerts therapeutic effects on social avoidance behavior after stress through activation of 5-HT2AR, but not preventive effects when administered before stress, suggesting that psilocin may promote stress resilience rather than resistance.
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
Cites 6
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Psychedelic Psychiatry's Brave New World. Cell April 1, 2020
- Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression ACS Chemical Neuroscience March 5, 2020
- In vitro and in vivo metabolism of psilocybin’s active metabolite psilocin Frontiers in Pharmacology April 29, 2024
- Pharmacokinetics of Psilocybin: A Systematic Review Pharmaceutics March 25, 2025
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