Psilocybin modulates nucleus accumbens activity via astrocytic transcriptional regulation
Su Min Kang, Dae-Si Kang, Tae-Yong Choi, Sejin Jeong, A-Hyeon Lee, Yujeong Jeong, Minjin Oh, Eum Ji Kim, Jieun Lee, Ki Jung Kim, Changjoon Justin Lee, Na Young Lim, Tae Woong Na, Bong Hyo Lee, Jae‐sung Bae, Sujeong Park, Suchan Chang, Jeansok John Kim
Experimental & molecular medicine November 5, 2026 DOI: 10.1038/s12276-026-01872-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Animals (species not specified in the abstract); nucleus accumbens tissue and cells |
| Interventions | Psilocybin Psilocin Psilocybin-like tryptamines |
| Measures | Ex vivo whole-cell recordings, extracellular GABA levels, intracellular GABA levels, ChIP–qPCR, calcium imaging |
| Topics | Psilocybin |
| Key points | Psilocybin-like tryptamines increased NAc neuronal activity while reducing extracellular GABA, and modulating NAc GABA receptor signaling altered psilocybin-appropriate responding. Psilocin reduced tonic (but not miniature synaptic) GABA currents in medium spiny neurons and selectively lowered astrocytic, not neuronal, intracellular GABA. The authors propose a model in which psilocybin regulates mesolimbic inhibitory tone via astrocyte-associated NFATc4/ALDH5A1-dependent GABA homeostasis. |
Abstract
Abstract Psilocybin is a serotonergic hallucinogen that acts primarily through 5-HT₂A receptor signaling, yet the mechanisms by which it regulates mesolimbic inhibitory tone remain poorly understood. Here we investigated how psilocybin and structurally related synthetic tryptamines modulate inhibitory signaling in the nucleus accumbens (NAc) and whether astrocyte-associated mechanisms contribute to this process. Psilocybin-like tryptamines that generalized to the psilocybin cue increased NAc neuronal activity while reducing extracellular GABA levels, identifying diminished NAc GABAergic tone as a neurochemical correlate of psilocybin-like behavioral responses. Consistent with this interpretation, local pharmacological modulation of NAc GABA receptor signaling altered psilocybin-appropriate responding. We next examined the cellular and molecular basis of this GABAergic regulation. Ex vivo whole-cell recordings revealed that psilocin, the active metabolite of psilocybin, reduced tonic GABA current in NAc medium spiny neurons without affecting miniature inhibitory postsynaptic currents, indicating preferential modulation of tonic rather than miniature synaptic inhibition. Cell-type-specific analyses further showed that psilocybin selectively reduced intracellular GABA levels in astrocytes, but not neurons. Psilocybin increased astrocytic NFATc4 and ALDH5A1 protein expression together with enhanced H3K27 acetylation, and ChIP–qPCR analysis showed increased NFATc4 occupancy at the Aldh5a1 promoter. Consistent with upstream serotonergic signaling, psilocin-induced calcium responses in astrocytes were attenuated by 5-HT₂A receptor antagonism. Together, these findings support a model in which psilocybin modulates mesolimbic inhibitory tone through astrocyte-associated regulation of NAc GABA homeostasis. Our findings further identify astrocytic NFATc4-associated transcriptional regulation as a mechanism linked to ALDH5A1 expression, astrocytic GABA homeostasis and tonic inhibitory regulation in the NAc.
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
Cites 20
- Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin Proceedings of the National Academy of Sciences January 23, 2012
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
- Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors Science February 16, 2023
- Psychedelics promote plasticity by directly binding to BDNF receptor TrkB Nature Neuroscience June 1, 2023
- 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
and 15 more in the library