The astrocytes in the prefrontal cortex contribute to the rapid antidepressant-like effects of psilocybin in the chronic restraint stress mouse model
Yong-xing Qiao, Wei Dai, Yi-shan Yao, Qian-Qian Wei, Chen-xing Yue, Yong-Yu Yin, Yun-Feng Li, Li-Ming Zhang
Progress in Neuro-Psychopharmacology and Biological Psychiatry April 1, 2026 DOI: 10.1016/j.pnpbp.2026.111698 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Chronic restraint stress (CRS) mouse model |
| Interventions | Psilocybin Ketamine |
| Topics | Psilocybin |
| Citations | 1 |
| Key points | Psilocybin rapidly reversed depressive-like behaviors in CRS mice and prevented astrocytic loss and increased C3 protein in the prefrontal cortex, with astrocyte depletion reducing its antidepressant action. |
Abstract
Psilocybin showed a rapid antidepressant response in several clinical trials, which offers new hope for treating depression. Astrocytes were associated with the etiology of depression and might contribute to the onset of psilocybin. In this study, we investigated the fast antidepressant effect of psilocybin and tested variations of GFAP (astrocytic markers) and C3 protein (markers of A1 astrocyte) expression after psilocybin treatment in the chronic restraint stress (CRS) mouse model. We next defined the modulating impact of psilocin (psilocybin's main active metabolite) on primary astrocytes as well as A1 astrocytes in vitro. The depletion of astrocytes was achieved by AAV injection to further verify the astrocytic role underlying the action of psilocybin. Psilocybin and ketamine (positive control) rapidly reversed the depressive-like behaviors in the CRS mice. Both psilocybin and ketamine inhibited the CRS-induced astrocytic loss and increased C3 protein in the prefrontal cortex (PFC). Psilocin up-regulated the activation and proliferation of primary astrocytes, and strengthened astrocytic ATP/lactate/glutamate release and mitochondrial function. Psilocin reversed A1 astrocyte-induced impairments in ATP/lactate/glutamate release and mitochondrial function. In vivo, depletion of astrocytes in the prelimbic (PrL) region of mPFC might affect the antidepressant action of psilocybin in unstressed mice. Our findings might be significant for a better understanding of astrocytic mechanisms in the action of psilocybin.
Comparable studies
Other preclinical and animal studies on psilocybin, 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 | |
| Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice | 2021 | Experimental study | |
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study |
Citations in the library
Cited by 2
- Current status and future prospects of research on psilocybin's regulation of neurotransmitters and their receptors related to the pathogenesis of tinnitus. Hearing research August 1, 2026
- Psychedelics and astrocytes: a hypothesis-driven perspective on neuro-glial integration, network plasticity, and neuroimmune reprogramming. Molecular Psychiatry August 11, 2026
Cites 11
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- 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
- Updating the dynamic framework of thought: Creativity and psychedelics. Neuroimage March 8, 2020
- DARK Classics in Chemical Neuroscience: Psilocybin ACS Chemical Neuroscience June 29, 2018
- Psychedelic drugs—a new era in psychiatry? Dialogues in Clinical Neuroscience June 30, 2019
and 6 more in the library