Institut national de la santé et de la recherche médicale, Grenoble Institut des Neurosciences, U1216, Université, Grenoble Alpes, Grenoble, France.
PLoS One. 2020 Sep 18;15(9):e0238156. doi: 10.1371/journal.pone.0238156. eCollection 2020.
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, but in vivo characterization 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 using TH-Cre rats. 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.
通过专门设计的药物激活的人工受体（DREADDs）代表了整合神经科学的技术革命。然而，最初使用的配体对其分子靶标表现出剂量依赖性的选择性，导致潜在的非特异性效应。最近提出了化合物 21（C21）作为替代品，但对其特性的体内表征还不够充分。在这里，我们使用 TH-Cre 大鼠评估了 C21 通过经典的 DREADD 受体 hM4Di 选择性调节黑质多巴胺能（DA）神经元活性的能力。在雄性中，1 mg.kg-1 的 C21 在对照动物中强烈增加了黑质神经元的活性，表明存在明显的脱靶效应。将剂量降低至 0.5 mg.kg-1 可避免这种非特异性效应，同时激活抑制性 DREADDs 并选择性降低黑质神经元的放电。在雌性中，0.5 mg.kg-1 的 C21 诱导短暂和残留的脱靶效应，可能减轻了抑制性 DREADDs 介导的效应。这项研究提出了在每种新的实验条件下测试所选配体的选择性和功效的必要性。
