Nature neuroscienceAug 7, 2026

Engineered mice designed to study how psychedelic drugs work

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Aug 8, 2026

Abstract

Psychedelic-induced behavioral changes in engineered mice validate their utility for studying the role of 5-hydroxytryptamine 2A receptors in psychedelic drug actions.

Engineered mice were created to identify HTR2A receptors and the cells containing them, revealing their distribution in the brain.
Electrophysiological studies showed that a specific psychedelic compound increased the firing rates of certain brain neurons.
The new mouse models could facilitate investigations into the complex mechanisms underlying the effects of psychedelics.

Simplified

Psychedelic drugs, such as lysergic acid diethylamide and psilocybin, have emerged as potentially transformative therapeutics for various neuropsychiatric conditions, including depression, anxiety, post-traumatic stress disorder, migraine and cluster headaches. Classical psychedelics exert their effects through activation of 5-hydroxytryptamine 2A receptors (HTR2As). Here we provide a suite of engineered mice that will be useful for clarifying the role of HTR2A in psychedelic drug actions. We generated Htr2a^EGFP-CreERT2 mice to identify both HTR2A-EGFP-CT receptors and HTR2A-containing cells, thereby revealing HTR2A distribution in the brain. We also generated humanized Htr2a^A242S^-EGFP-Cre and constitutive Htr2a^Cre mice. Psychedelic-induced behavioral changes in these mice validated their utility for these studies. Electrophysiological investigations on brain sections from these mice revealed that 2,5,-dimethoxy-4-iodoamphetamine induced robust increases in firing of genetically identified pyramidal neurons. These mouse lines are valuable tools for investigating the molecular, cellular, pharmacological, physiological, behavioral and other mechanisms of psychedelic actions in vivo.