5‐HT 2A receptors in the prelimbic cortex VIP‐expressing interneurons: A mechanism for psychedelic‐induced innate fear attenuation

Abstract Background and Purpose Fear‐related psychiatric disorders such as phobias and anxiety are insufficiently treated by current therapies. Psychedelics targeting 5‐HT₂ A 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. Experimental Approach 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. Key Results 4‐AcO‐DMT significantly suppressed TMT evoked 22‐kHz USVs via 5‐HT₂ A 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‐HT₂ A receptor‐driven vasoactive intestinal polypeptide (VIP) interneuron engagement—is critical to 4‐AcO‐DMT ‐induced suppression of innate fear responses. Conclusion and Implications Our study reveals that 5‐HT₂ A 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. LINKED ARTICLES 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