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Papers: 7 Oct 2023 - 13 Oct 2023

2023 Sep 26



A suite of engineered mice for interrogating psychedelic drug actions.


Chiu YT, Deutch AY, Wang W, Schmitz GP, Huang KL, Kocak DD, Llorach P, Bowyer K, Liu B, Sciaky N, Hua K, Chen C, Mott SE, Niehaus J, DiBerto JF, English J, Walsh JJ, Scherrer G, Herman MA, Wu Z, Wetsel WC, Roth BL


Psychedelic drugs like lysergic acid diethylamide (LSD) and psilocybin have emerged as potentially transformative therapeutics for many neuropsychiatric diseases, including depression, anxiety, post-traumatic stress disorder, migraine, and cluster headaches. LSD and psilocybin exert their psychedelic effects via activation of the 5-hydroxytryptamine 2A receptor (HTR2A). Here we provide a suite of engineered mice useful for clarifying the role of HTR2A and HTR2A-expressing neurons in psychedelic drug actions. We first generated -EGFP-CT-IRES-CreERT2 mice (CT:C-terminus) to independently identify both HTR2A-EGFP-CT receptors and HTR2A-containing cells thereby providing a detailed anatomical map of HTR2A and identifying cell types that express HTR2A. We also generated a humanized mouse line and an additional constitutive -Cre mouse line. Psychedelics induced a variety of known behavioral changes in our mice validating their utility for behavioral studies. Finally, electrophysiology studies revealed that extracellular 5-HT elicited a HTR2A-mediated robust increase in firing of genetically-identified pyramidal neurons–consistent with a plasma membrane localization and mode of action. These mouse lines represent invaluable tools for elucidating the molecular, cellular, pharmacological, physiological, behavioral, and other actions of psychedelic drugs .