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 Peer reviewed DOI: 10.1111/bph.70307 via PubMed
Summary
4-AcO-DMT suppresses innate fear responses in rats, specifically reducing predator odor-evoked 22-kHz ultrasonic vocalizations (USVs). The study found that this suppression is mediated through the activation of 5-HT₂A receptors and involves the recruitment of vasoactive intestinal polypeptide (VIP) interneurons in the prelimbic cortex. Chemogenetic activation of these interneurons eliminated the behavioral effects, highlighting their critical role in the mechanism of fear attenuation by 4-AcO-DMT.
Study at a glance
| Population | rats |
|---|---|
| Key finding | 4-AcO-DMT significantly suppressed TMT evoked 22-kHz USVs via 5-HT₂A receptor activation. |
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.