This preclinical rat study (n=24; 8 rats per group) shows that a single dose of psilocybin (1.0 mg/kg) or the selective 5-HT2A receptor agonist 25CN-NBOH (1.5 mg/kg) reduces immobility in the forced-swim test, with effects persisting for at least three months. Electrophysiology of medial prefrontal cortex (mPFC) Layer 5 neurons reveals long-lasting functional, but not structural, plasticity—characterised by changes in resting membrane potential, neuronal firing rates, and excitatory synaptic input. In contrast, dendritic spine density and gene-expression markers related to synaptic structure remain unchanged, indicating enduring functional alterations rather than persistent structural modifications.
Abstract of Psychedelics produce enduring behavioral effects and functional plasticity through mechanisms independent of structural plasticity
“Activation of serotonin 2A (5-HT2A) receptors is thought to underly the long-lasting antidepressant effects of psychedelics such as psilocybin, but beyond that, the molecular and cellular mechanisms involved are not well understood. Recent preclinical studies using mice have primarily examined relatively short time points after psychedelic administration, which does not address the long-lasting effects of psilocybin in humans (i.e., several months or more). We utilized a rat experimental system to demonstrate that both psilocybin and the selective 5-HT2A receptor agonist 25CN-NBOH reduce immobility in the forced swim test without a decrease in effect size for at least three months after a single administration of the psychedelic. There were no overt behavioral differences between psilocybin and 25CN-NBOH treated animals, suggesting 5-HT2A receptor activation is sufficient to produce long-lasting behavioral changes. Functional cellular plasticity in neurons from the medial prefrontal cortex (mPFC) of these animals was assessed using brain slice electrophysiology. Functional plasticity was evident for both psychedelics several months after treatment, and Layer 5 excitatory pyramidal neurons demonstrated significant changes in resting membrane potential, firing rates, and synaptic excitation. Recorded neurons were examined by microscopy for synaptic density and spine classification, which found no differences between control and psychedelic-treated. Gene expression studies for several presynaptic and postsynaptic markers in the mPFC indicated no differences in expression between groups. Together, our results indicate a single treatment with a psychedelic is sufficient to elicit very long-lasting behavioral and cellular changes through enduring function plasticity rather than structural plasticity.“
Authors: Hannah M. Kramer, Meghan Hibicke, Jason Middleton, Alaina M. Jaster, Jesper L. Kristensen & Charles D. Nichols
Summary of Psychedelics produce enduring behavioral effects and functional plasticity through mechanisms independent of structural plasticity
The introduction outlines growing scientific interest in psilocybin, a naturally occurring tryptamine found in certain mushrooms, because of its unusually long-lasting antidepressant effects in humans. Clinical reports indicate benefits that can persist for months or even years after only one or two doses. The authors explain that while psilocybin is moving towards regulatory approval, researchers still do not understand how a single administration can give rise to such durable therapeutic outcomes. Earlier research has shown that psychedelics can acutely influence gene expression, increase synaptic proteins, and stimulate the formation of dendritic spines—tiny structures on neurons associated with learning and memory. These effects have been seen across several animal models, including rats, mice and pigs. Some work has also identified short-term increases in spine growth in areas such as the prefrontal cortex. However, very few studies have examined whether these structural changes, or other biological processes, persist for months, which is the timescale relevant for human therapeutic effects.
The authors highlight two central questions. First, do the structural changes observed shortly after psychedelic exposure persist over several months? Second, is direct activation of the serotonin 2A receptor (5-HT2A) sufficient to produce long-lasting effects, or are other receptors also required? To explore this, they used the Wistar Kyoto rat, a model chosen because it naturally displays behavioural features that resemble human depression, including a tendency towards passive coping strategies. The study compared psilocybin with 25CN-NBOH, a highly selective 5-HT2A receptor agonist, to see whether both compounds produced similarly persistent behavioural and neural effects. The authors assessed behaviour using the forced swim test, then measured long-term changes in synaptic proteins, neuronal physiology and dendritic structure within the medial prefrontal cortex (mPFC), focusing especially on the infralimbic region, which previous studies suggest is strongly linked to antidepressant-like behaviour.
Methods
General approach
The study used male rats randomly assigned to receive saline, psilocybin, or 25CN-NBOH, with eight animals in each group. Only males were used because current literature has not sufficiently characterised depression-like traits in females for this particular strain. Rats were housed under standard laboratory conditions with access to food, water and environmental enrichment. Psilocybin and 25CN-NBOH were administered as a single intraperitoneal injection on day 0 at doses selected to match behaviourally relevant ranges from earlier research.
Behavioural testing
Find this paper
https://doi.org/10.1038/s41386-025-02272-3
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Cite this paper (APA)
Kramer, H. M., Hibicke, M., Middleton, J., Jaster, A. M., Kristensen, J. L., & Nichols, C. D. (2025). Psychedelics produce enduring behavioral effects and functional plasticity through mechanisms independent of structural plasticity. Neuropsychopharmacology, 1-9.
Study details
Compounds studied
Psilocybin
Placebo
Topics studied
Neuroscience
Study characteristics
Placebo-Controlled
Animal Study
Bio/Neuro
Participants
24
Rodents
Compound Details
The psychedelics given at which dose and how many times
Psilocybin 1.0 mg | 1x