A suite of engineered mice for interrogating psychedelic drug actions
OpenAlex – September 26, 2023
Source: OpenAlex
Summary
Psychedelic drugs, including LSD, offer significant potential for treating neuropsychiatric conditions. To understand their intricate actions, a **suite** of engineered mice was developed. These models allow for precise mapping of key brain receptors and the cells they influence, crucial for **Neuroscience and Neuropharmacology Research**. Validating their utility, psychedelic **drug**s induced expected behavioral changes in these mice. Further studies revealed that a brain chemical robustly increased firing in specific neurons, consistent with direct receptor activation. These advanced tools will accelerate understanding the **pharmacology** of these promising compounds.
Abstract
ABSTRACT 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 Htr2a -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 Htr2a mouse line and an additional constitutive Htr2A -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 in vivo .