The Selective 5HT2A Receptor Agonist, 25CN-NBOH Exerts Excitatory and Inhibitory Cellular Actions on Mouse Medial Prefrontal Cortical Neurons.
Yang Wang, Jesper L. Kristensen, Kristi A. Kohlmeier
Synapse March 1, 2025 DOI: 10.1002/syn.70014 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mouse brain slices containing medial prefrontal cortex pyramidal neurons |
| Intervention | 25CN-NBOH |
| Dose | 10 µM and 200 nM |
| Duration | Acute (minutes) and longer-term (1 hour) exposure |
| Topics | Serotonin |
| Keywords | Action potential Brain slices Electrophysiological recordings Psychedelics |
| Citations | 5 |
| Key findings | 25CN-NBOH enhances excitatory synaptic transmission via serotonin 2A receptors but suppresses neuronal firing via M-current channels, revealing a dual action on mPFC pyramidal neurons. |
Abstract
Psychedelic compounds have gained renewed interest due to their rapid and long-lasting therapeutic effects on stress-related disorders. While the underlying mechanisms of therapeutic actions of psychedelic compounds are still unclear, these drugs are thought to modulate the activity of the serotonergic system, primarily through activating serotonin type 2A receptor (5-HT2AR) and studies have focused on these actions in the medial prefrontal cortex (mPFC). 25CN-NBOH, a synthetic psychedelic compound with a high binding affinity for 5-HT2ARs and anti-anxiety actions, has emerged as a valuable tool for investigating the physiological functions mediated by this receptor. This study aimed to investigate the electrophysiological effects of 25CN-NBOH on pyramidal mPFC neurons using whole-cell patch clamp recordings in mouse brain slices. We recorded synaptic events and action potential rates during acute and long-term exposure to two concentrations of 25CN-NBOH. Acute application of 10 µM 25CN-NBOH increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) that was reliant on activation of 5-HT2AR, and which was not seen upon chronic exposure. A similar effect of 200 nM 25CN-NBOH was not noted. Surprisingly, both 10 µM and 200 nM 25CN-NBOH significantly suppressed the firing rate following acute as well as a longer-term exposure of 1 h. This suppression was independent of 5-HT2AR activation but was mediated by M-current channels, as evidenced by the reversal of suppression with the M-current blocker XE-991. Our data suggest a complicated dual action of 25CN-NBOH in enhancing excitatory transmission while also reducing excitability. Our data contribute to knowledge regarding the cellular consequence of 5-HT2AR agonism and contribute to widening our understanding of the potential mechanisms underlying the therapeutic actions of serotonergic psychedelics.
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
Cited by 6
- The utility of 2,5-dimethoxy-4-iodoamphetamine for the study of serotonin 2A and 2C receptors. Molecular Pharmacology 2026
- Psychedelics Reverse the Polarity of Long-Term Synaptic Plasticity in Cortical-Projecting Claustrum Neurons eNeuro October 1, 2025
- Electrophysiological mechanisms of psychedelic drugs: A systematic review. Neuroscience & Biobehavioral Reviews June 1, 2026
- Hippocampal synaptic transmission and Ca2⁺ signaling are altered by the selective 5-HT2A receptor agonist, 25CN-NBOH. Neuroscience August 30, 2026
- Cellular mechanisms of serotonergic psychedelics - apical hypercontextualisation. Neuroscience & Biobehavioral Reviews July 1, 2026
and 1 more in the library
Cites 22
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- 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
- Control of Serotonergic Function in Medial Prefrontal Cortex by Serotonin-2A Receptors through a Glutamate-Dependent Mechanism Journal of Neuroscience December 15, 2001
- Psychedelic Psychiatry's Brave New World. Cell April 1, 2020
and 17 more in the library