Compound 21, a two-edged sword with both DREADD-selective and off-target outcomes in rats

被引：25

作者：

Goutaudier, Raphael ^{[1
]}

Coizet, Veronique ^{[1
]}

Carcenac, Carole ^{[1
]}

Carnicella, Sebastien ^{[1
]}

机构：

[1] Univ Grenoble Alpes, Grenoble Inst Neurosci, U1216, INSERM, Grenoble, France

来源：

PLOS ONE | 2020年 / 15卷 / 09期

关键词：

VENTRAL TEGMENTAL AREA; SUBSTANTIA-NIGRA; SUPERIOR COLLICULUS; DOPAMINE; CHEMOGENETICS; ACTIVATION; NEURONS; BEHAVIOR;

D O I：

10.1371/journal.pone.0238156

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) represent a technical revolution in integrative neuroscience. However, the first used ligands exhibited dose-dependent selectivity for their molecular target, leading to potential unspecific effects. Compound 21 (C21) was recently proposed as an alternative, butin vivocharacterization of its properties is not sufficient yet. Here, we evaluated its potency to selectively modulate the activity of nigral dopaminergic (DA) neurons through the canonical DREADD receptor hM4Di usingTH-Crerats. In males, 1 mg.kg(-1)of C21 strongly increased nigral neurons activity in control animals, indicative of a significant off-target effect. Reducing the dose to 0.5 mg.kg(-1)circumvented this unspecific effect, while activated the inhibitory DREADDs and selectively reduced nigral neurons firing. In females, 0.5 mg.kg(-1)of C21 induced a transient and residual off-target effect that may mitigated the inhibitory DREADDs-mediated effect. This study raises up the necessity to test selectivity and efficacy of chosen ligands for each new experimental condition.

引用

页数：11

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