The catecholamine neurotransmitter dopamine (DA) exerts powerful modulatory control of physiology and behavior across phylogeny. Perturbations of DA signaling in humans are associated with multiple neurodegenerative and behavioral disorders, including Parkinson's disease, attention-deficit/hyperactivity disorder, addiction and schizophrenia. In the nematode C. elegans, DA signaling regulates mating behavior, learning, food seeking and locomotion. Previously, we demonstrated that loss of function mutations in the dat-1 gene that encodes the presynaptic DA transporter (DAT-1) results in a rapid cessation of movement when animals are placed in water, termed Swimming Induced Paralysis (Swip). Loss of function mutations in genes that support DA biosynthesis, DA vesicular packaging and DA action at the extrasynaptic D2-type DA receptor DOP-3 suppress Swip in dat-1 animals, consistent with paralysis as arising from excessive DA signaling. Although animals grown on the vesicular monoamine transporter antagonist reserpine diminish Swip, the drug must be applied chronically, can impact the signaling of multiple biogenic amines, and has been reported to have penetrant, off-target actions. Here, we demonstrate that the antipsychotic drug azaperone potently and rapidly suppresses Swip behavior in either dat-1 mutants, as well as in wildtype animals treated with the DAT-1 antagonist nisoxetine, with genetic experiments consistent with DOP-3 antagonism as the mechanism of Swip suppression. Reversal of Swip in previously paralyzed dat-1 animals by azaperone application demonstrates an otherwise functionally-intact swimming circuit in these mutants. Finally, whereas azaperone suppresses DA-dependent Swip, the drug fails to attenuate the DA-independent paralysis induced by βPEA, aldicarb or genetic disruption of γ-aminobutyric acid (GABA) signaling. We discuss our findings with respect to the use of azaperone as a potent and selective tool in the identification and analysis of presynaptic mechanisms that regulate DA signaling.

中文翻译：

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抗精神病药和D2型多巴胺受体拮抗剂azaperone可以阻断和逆转秀丽隐杆线虫游泳诱发的瘫痪。

儿茶酚胺神经递质多巴胺（DA）在整个系统发育过程中发挥强大的生理和行为调控功能。DA信号在人类中的摄动与多种神经退行性和行为障碍有关，包括帕金森氏病，注意力缺陷/多动症，成瘾和精神分裂症。在线虫秀丽隐杆线虫中，DA信号调节交配行为，学习，觅食和运动。以前，我们证明了将dat-1基因编码的突触前DA转运蛋白（DAT-1）的功能突变丢失会导致动物在水中放置时运动的迅速停止，这种运动被称为游泳诱发麻痹（Swip）。支持DA生物合成的基因中的功能突变丧失，DA囊泡包装和对突触外D2型DA受体DOP-3的DA作用抑制了dat-1动物的Swip，这与过量DA信号引起的瘫痪相一致。尽管在水泡单胺转运蛋白拮抗剂利血平上生长的动物会减少Swip，但该药物必须长期使用，会影响多种生物胺的信号传导，并且据报道具有渗透性，脱靶作用。在这里，我们证明了抗精神病药物阿扎哌隆有效并迅速抑制dat-1突变体以及用DAT-1拮抗剂尼西西汀治疗的野生型动物中的Swip行为，其基因实验与DOP-3拮抗作用一致，是DAT-3拮抗作用的机制。刷卡抑制。通过使用氮杂哌酮逆转先前瘫痪的dat-1动物中的Swip，可以证明这些突变体中的功能完整的游泳循环。最后，尽管氮杂哌酮抑制DA依赖性Swip，但该药物未能减轻由βPEA，涕灭威或γ-氨基丁酸（GABA）信号转导的遗传干扰所引起的DA依赖性麻痹。我们讨论我们的发现，关于使用氮杂哌酮作为有效和选择性的工具，用于鉴定和分析调节DA信号的突触前机制。