INSERM UMR-S 1270, Paris, France.
Faculty of Sciences and Engineering, Sorbonne University, Paris, France.
Eur J Neurosci. 2021 Aug;54(4):5327-5340. doi: 10.1111/ejn.15394. Epub 2021 Jul 29.
Dopamine D1 receptors play an important role in the effects of cocaine. Here, we investigated the role of neurons which express these receptors (D1-neurons) in the acute locomotor effects of cocaine and the locomotor sensitization observed after a second injection of this drug, using the previously established two-injection protocol of sensitization. We inhibited D1-neurons using double transgenic mice conditionally expressing the inhibitory Gi-coupled designer receptor exclusively activated by designer drugs (Gi-DREADD) in D1-neurons. Chemogenetic inhibition of D1-neurons by a low dose of clozapine (0.1 mg/kg) decreased the cocaine-induced expression of Fos in striatal neurons. It diminished the basal locomotor activity and acute hyper-locomotion induced by cocaine (20 mg/kg). Clozapine 0.1 mg/kg had no effect by itself and did not alter cocaine effects in wild-type mice. Inhibition of D1-neurons during the first cocaine administration prevented the sensitization of the locomotor response in response to a second cocaine administration 10 days later. On Day 11, inhibition of D1-neurons by clozapine stimulation of Gi-DREADD blocked cocaine-induced locomotion including in sensitized mice, whereas on Day 12, in the absence of clozapine and D1-neurons inhibition, all mice displayed a sensitized response to cocaine. These results show that chemogenetic inhibition of D1-neurons decreases spontaneous and cocaine-induced locomotor activity. It prevents sensitization induction and blocks sensitized locomotion in a two-injection protocol of sensitization but does not reverse established sensitization. Our study further supports the central role of D1-neurons in mediating the acute locomotor effects of cocaine and its sensitization.
多巴胺 D1 受体在可卡因的作用中发挥着重要作用。在这里，我们使用先前建立的敏化双注射方案，研究了表达这些受体（D1 神经元）的神经元在可卡因的急性运动效应和第二次注射这种药物后观察到的运动敏化中的作用。我们使用条件性表达抑制性 Gi 偶联的 Designer 药物（Gi-DREADD）的双转基因小鼠抑制 D1 神经元，这种 Designer 药物专门激活神经元。低剂量氯氮平（0.1mg/kg）对 D1 神经元的化学遗传抑制减少了纹状体神经元中 Fos 的表达。它减弱了基础运动活动和可卡因（20mg/kg）引起的急性过度运动。氯氮平 0.1mg/kg 本身没有作用，也不会改变野生型小鼠对可卡因的作用。在第一次可卡因给药期间抑制 D1 神经元可防止 10 天后第二次可卡因给药引起的运动反应敏化。在第 11 天，通过刺激 Gi-DREADD 抑制 D1 神经元阻断了可卡因诱导的运动，包括在敏化小鼠中，而在第 12 天，在没有氯氮平和 D1 神经元抑制的情况下，所有小鼠对可卡因表现出敏化反应。这些结果表明，化学遗传抑制 D1 神经元可降低自发和可卡因诱导的运动活动。它可防止敏化诱导并阻断敏化双注射敏化方案中的运动，但不能逆转已建立的敏化。我们的研究进一步支持 D1 神经元在介导可卡因的急性运动效应及其敏化中的核心作用。
