5-HT2A receptors in the prelimbic cortex VIP-expressing interneurons: A mechanism for psychedelic-induced innate fear attenuation.
Yuanyuan Wang, Yishan Yao, Ruibin Su, Haitao Yan
British Journal of Pharmacology July 1, 2026 DOI: 10.1111/bph.70307 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | 4-Acetoxy-N N-dimethyltryptamine (4-AcO-DMT) |
| Topics | Serotonin |
| Keywords | 4‐Aco‐DMT Innate fear Psychedelics Trimethylthiazoline Ultrasonic vocalizations |
| Citations | 1 |
| Key findings | 4-AcO-DMT suppresses innate fear responses in rats by activating 5-HT₂A receptors, which engage VIP interneurons in the prelimbic cortex. |
Abstract
Fear-related psychiatric disorders such as phobias and anxiety are insufficiently treated by current therapies. Psychedelics targeting 5-HT₂A receptors show promise in modulating fear circuits, but their specific neurobiological substrates remain unclear. This study investigates the effects of 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT), a psychedelic compound, on innate fear responses and elucidates its underlying cortical microcircuits, focusing on predator odour-evoked 22-kHz ultrasonic vocalizations (USVs) in rats. Using an optimized paradigm of 2,4,5-trimethylthiazoline (TMT)-induced 22-kHz USVs in rats, the effects of 4-AcO-DMT were evaluated, and the dose-response relationships were investigated. In behavioural experiments, we demonstrated that 4-AcO-DMT suppresses 22-kHz USVs by reducing fear-related response in rats. Brain-wide EGR1 expression and targeted brain region lesions were employed to identify the brain region through which 4-AcO-DMT acts. Specific neuronal ablation and chemogenetic manipulation were applied to determine the types of neurons modulated by 4-AcO-DMT, and receptor antagonism and localized receptor knockout strategies were used to identify the receptor subtypes involved. 4-AcO-DMT significantly suppressed TMT evoked 22-kHz USVs via 5-HT₂A receptor activation. This fear attenuation was mediated by recruitment of VIP interneurons in the prelimbic cortex (PrL), as chemogenetic activation of these cells abolished the behavioural effect. A cortical microcircuit mechanism-5-HT₂A receptor-driven vasoactive intestinal polypeptide (VIP) interneuron engagement-is critical to 4-AcO-DMT -induced suppression of innate fear responses. Our study reveals that 5-HT₂A receptor activation by 4-AcO-DMT suppresses innate fear through VIP interneuron-mediated modulation in the prelimbic cortex, advancing the neurobiological understanding of serotonergic psychedelics. This article is part of a themed issue Emerging Therapeutic Opportunities for Psychedelic and Related Drugs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v183.14/issuetoc.
Comparable studies
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| 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 |