Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA.
Neurochem Res. 2022 Jan;47(1):177-189. doi: 10.1007/s11064-021-03275-4. Epub 2021 Feb 25.
The dopamine transporter (DAT) mediates the inactivation of released dopamine (DA) through its reuptake, and thereby plays an important homeostatic role in dopaminergic neurotransmission. Amphetamines exert their stimulant effects by targeting DAT and inducing the reverse transport of DA, leading to a dramatic increase of extracellular DA. Animal models have proven critical to investigating the molecular and cellular mechanisms underlying transporter function and its modulation by psychostimulants such as amphetamine. Here we establish a behavioral model for amphetamine action using adult Drosophila melanogaster. We use it to characterize the effects of amphetamine on sleep and sleep architecture. Our data show that amphetamine induces hyperactivity and disrupts sleep in a DA-dependent manner. Flies that do not express a functional DAT (dDAT null mutants) have been shown to be hyperactive and to exhibit significantly reduced sleep at baseline. Our data show that, in contrast to its action in control flies, amphetamine decreases the locomotor activity of dDAT null mutants and restores their sleep by modulating distinct aspects of sleep structure. To begin to explore the circuitry involved in the actions of amphetamine on sleep, we also describe the localization of dDAT throughout the fly brain, particularly in neuropils known to regulate sleep. Together, our data establish Drosophila as a robust model for studying the regulatory mechanisms that govern DAT function and psychostimulant action.
多巴胺转运体（DAT）通过再摄取来介导已释放多巴胺（DA）的失活，从而在多巴胺能神经传递中发挥重要的动态平衡作用。安非他命通过靶向 DAT 并诱导 DA 的反向转运发挥其兴奋剂作用，导致细胞外 DA 显著增加。动物模型已被证明对研究转运体功能的分子和细胞机制及其被安非他命等精神兴奋剂的调节至关重要。在这里，我们使用成年黑腹果蝇建立了安非他命作用的行为模型。我们用它来描述安非他命对睡眠和睡眠结构的影响。我们的数据表明，安非他命以依赖 DA 的方式诱导过度活跃和破坏睡眠。已经表明不表达功能性 DAT（dDAT 缺失突变体）的果蝇表现出过度活跃，并在基线时表现出明显减少的睡眠。我们的数据表明，与在对照果蝇中的作用相反，安非他命通过调节睡眠结构的不同方面，降低 dDAT 缺失突变体的运动活性并恢复其睡眠。为了开始探索涉及安非他命对睡眠作用的电路，我们还描述了 dDAT 在整个果蝇大脑中的定位，特别是在已知调节睡眠的神经节中。总之，我们的数据确立了果蝇作为研究调节 DAT 功能和精神兴奋剂作用的调控机制的强大模型。
