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A suite of engineered mice for interrogating psychedelic drug actions
Yi-Ting Chiu1, Ariel Y Deutch2,3, Wei Wang4
1Department of Pharmacology, University of North Carolina at Chapel Hill, NC 27599, USA.
Biorxiv : the Preprint Server for Biology
|October 9, 2023
Summary
Engineered mouse models, including humanized HTR2A mice, aid in studying psychedelic drugs like LSD and psilocybin. These tools help clarify the role of the serotonin 5-HT2A receptor in psychedelic effects and therapeutic potential.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Psychedelic compounds, such as lysergic acid diethylamide (LSD) and psilocybin, show promise for treating neuropsychiatric disorders.
- These psychedelics primarily act through the 5-hydroxytryptamine 2A receptor (HTR2A).
Purpose of the Study:
- To develop and validate novel mouse models for studying the mechanisms of psychedelic drug action.
- To clarify the role of HTR2A and HTR2A-expressing neurons in the effects of psychedelic compounds.
Main Methods:
- Generation of HTR2A-EGFP-CT-IRES-CreERT2 mice for receptor and cell identification.
- Creation of a humanized HTR2A mouse line and a constitutive HTR2A-Cre mouse line.
- Behavioral studies and electrophysiology to assess drug effects and receptor function.
Main Results:
- The engineered mice exhibited known behavioral responses to psychedelics, confirming their utility.
- Electrophysiology demonstrated HTR2A-mediated increases in pyramidal neuron firing in response to 5-HT.
- Detailed anatomical mapping of HTR2A expression in various cell types was achieved.
Conclusions:
- These specialized mouse lines are essential tools for understanding the molecular, cellular, and behavioral effects of psychedelic drugs.
- They facilitate research into the therapeutic mechanisms of psychedelics for neuropsychiatric conditions.
- The study validates the use of these models for in vivo investigation of HTR2A-mediated psychedelic pharmacology.
