PPubMed11 Oct 2019Cited 38×

DREADDs: The Power of the Lock, the Weakness of the Key. Favoring the Pursuit of Specific Conditions Rather than Specific Ligands Off-Target Effects of DREADD Ligands

Raphaël Goutaudier, Véronique Coizet, Carole Carcenac, Sebastien Carnicella

Abstract

'Sebastien Carnicella'] Title: Visual Abstract

A figure from DREADDs: The Power of the Lock, the Weakness of the Key. Favoring the Pursuit of Specific Conditions Rather than Specific Ligands Off-Target Effects of DREADD Ligands — fig. from the paper

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DREADD ligands often cause off‑target effects; rigorous validation and proper controls are essential for reliable chemogenetic experiments.

What’s new

i.Identification of off‑target effects of commonly used DREADD ligands (CNO, clozapine, C21, JHU compounds)
ii.Presentation of a three‑step validation framework for ligand selection, dosing, and control experiments
iii.Critical review of alternative chemogenetic tools (KORD, LGICs) and their limitations
iv.Summary of pharmacokinetic data showing C21 CSF levels >10× EC50 at 3 mg/kg
v.Emphasis on the necessity of using DREADD‑negative controls in behavioral studies

How they did it

The authors performed a comprehensive literature review of studies on DREADD ligands, pharmacokinetics, and behavioral effects, and synthesized the findings into practical guidelines. They also proposed a three‑step experimental validation workflow.

What they found

Systemic CNO at 10 mg/kg induces behavioral effects in rats and mice independent of DREADDs
Low‑dose clozapine (0.1 mg/kg) increases anxiety‑related behavior in mice and rats
C21 at 3 mg/kg yields CSF concentrations (~40 nM) >10× the EC50 (3 nM) for DREADD activation without back‑metabolism to clozapine
C21 at 1 mg/kg can alter brain function in wild‑type mice, indicating potential off‑target activity
JHU37152 and JHU37160 show higher in‑vivo potency for DREADDs but retain affinity for endogenous receptors

Caveats

✕New DREADD ligands (C21, JHU compounds) remain poorly characterized in vivo
✕Off‑target effects may vary with species, strain, sex, and experimental conditions
✕Complete selectivity for DREADDs is unlikely due to structural similarity with endogenous GPCRs
✕Lack of standardized protocols for ligand dosing and control experiments

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DREADDs: The Power of the Lock, the Weakness of the Key. Favoring the Pursuit of Specific Conditions Rather than Specific Ligands Off-Target Effects of DREADD Ligands

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