Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, 94143, USA.
Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, 02129, USA.
Nat Commun. 2019 Sep 9;10(1):4078. doi: 10.1038/s41467-019-11936-w.
Anesthetics are generally associated with sedation, but some anesthetics can also increase brain and motor activity-a phenomenon known as paradoxical excitation. Previous studies have identified GABA receptors as the primary targets of most anesthetic drugs, but how these compounds produce paradoxical excitation is poorly understood. To identify and understand such compounds, we applied a behavior-based drug profiling approach. Here, we show that a subset of central nervous system depressants cause paradoxical excitation in zebrafish. Using this behavior as a readout, we screened thousands of compounds and identified dozens of hits that caused paradoxical excitation. Many hit compounds modulated human GABA receptors, while others appeared to modulate different neuronal targets, including the human serotonin-6 receptor. Ligands at these receptors generally decreased neuronal activity, but paradoxically increased activity in the caudal hindbrain. Together, these studies identify ligands, targets, and neurons affecting sedation and paradoxical excitation in vivo in zebrafish.
麻醉剂通常与镇静作用相关，但一些麻醉剂也可以增加大脑和运动活动——这种现象被称为矛盾兴奋。先前的研究已经确定 GABA 受体是大多数麻醉药物的主要靶标，但这些化合物如何产生矛盾兴奋尚不清楚。为了鉴定和理解这些化合物，我们应用了一种基于行为的药物分析方法。在这里，我们显示出一组中枢神经系统抑制剂会导致斑马鱼出现矛盾兴奋。我们使用这种行为作为读出，筛选了数千种化合物，并鉴定出数十种引起矛盾兴奋的化合物。许多命中化合物调节人类 GABA 受体，而其他化合物似乎调节不同的神经元靶点，包括人类血清素-6 受体。这些受体的配体通常会降低神经元活性，但在尾髓后脑却会反常地增加活性。总之，这些研究鉴定了在斑马鱼体内影响镇静和矛盾兴奋的配体、靶标和神经元。
