可卡因通过多巴胺 D2R 和 PPARγ 激活介导纹状体的昼夜节律重编程。
Cocaine-mediated circadian reprogramming in the striatum through dopamine D2R and PPARγ activation.
机构信息
Center for Epigenetics and Metabolism, INSERM U1233, Department of Microbiology and Molecular Genetics, University of California Irvine, Irvine, CA, 92697, USA.
Center for Epigenetics and Metabolism, INSERM U1233, Department of Biological Chemistry, University of California Irvine, Irvine, CA, 92697, USA.
出版信息
Nat Commun. 2020 Sep 7;11(1):4448. doi: 10.1038/s41467-020-18200-6.
Substance abuse disorders are linked to alteration of circadian rhythms, although the molecular and neuronal pathways implicated have not been fully elucidated. Addictive drugs, such as cocaine, induce a rapid increase of dopamine levels in the brain. Here, we show that acute administration of cocaine triggers reprogramming in circadian gene expression in the striatum, an area involved in psychomotor and rewarding effects of drugs. This process involves the activation of peroxisome protein activator receptor gamma (PPARγ), a nuclear receptor involved in inflammatory responses. PPARγ reprogramming is altered in mice with cell-specific ablation of the dopamine D2 receptor (D2R) in the striatal medium spiny neurons (MSNs) (iMSN-D2RKO). Administration of a specific PPARγ agonist in iMSN-D2RKO mice elicits substantial rescue of cocaine-dependent control of circadian genes. These findings have potential implications for development of strategies to treat substance abuse disorders.
物质滥用障碍与昼夜节律的改变有关，尽管涉及的分子和神经元途径尚未完全阐明。成瘾药物，如可卡因，会导致大脑中多巴胺水平的快速升高。在这里，我们表明，可卡因的急性给药会触发纹状体中昼夜节律基因表达的重编程，纹状体是参与药物的运动和奖励效应的区域。这个过程涉及过氧化物酶体蛋白激活物受体γ（PPARγ）的激活，PPARγ 是一种参与炎症反应的核受体。在纹状体中型多棘神经元（MSNs）中特异性敲除多巴胺 D2 受体（D2R）的小鼠中，PPARγ 重编程发生改变（iMSN-D2RKO）。在 iMSN-D2RKO 小鼠中给予特定的 PPARγ 激动剂会引起对可卡因依赖的昼夜节律基因控制的显著挽救。这些发现可能对开发治疗物质滥用障碍的策略具有重要意义。
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