A Molecular Method to Selectively Record Activation of Dopamine Receptor Subtypes

神经元通过分泌一种叫做神经递质的化学信号来相互交流。从一个神经元分泌的神经递质与其他细胞膜上的特定受体结合，并在这些细胞中引起一连串的反应。多巴胺是一种调节多种生物过程的神经递质，包括认知和情感、动机和奖励、运动和某些激素的释放。多巴胺系统失衡与精神分裂症、双相情感障碍、注意缺陷多动障碍、妥瑞氏综合征、成瘾、帕金森病和高血压等多种疾病有关。哺乳动物基因组编码五种不同的多巴胺受体，根据它们的细胞信号传导和序列同源性，可以将它们分为两类。不同类型的受体被认为介导不同的生物学功能，并涉及不同的疾病。这两类多巴胺受体也可以从药理学上加以区分，但这种区分不是绝对的。此外，在同一类受体之间进行药理学区分要困难得多。一种给定的药物通常作用于多个受体，产生不必要的副作用。因此，拥有针对各种多巴胺受体的高度特异性药物对于成功治疗涉及特定多巴胺受体类型且副作用最小的疾病至关重要。由于许多神经元表达多种类型的多巴胺受体，目前还不可能将特定药物的作用归因于特定受体。在临床上，这种知识差距转化为无法预测和解决给定药物的副作用。在这里，我们提出了一种新的分子方法来选择性地记录小鼠大脑中特定多巴胺受体亚型的激活。由于我们的系统具有极强的选择性，它可以用来明确地确定哪种受体亚型在特定的神经元中被激活，以响应给定的药物。不管这个神经元中是否存在其他种类的多巴胺受体，这个过程都是完成的。我们将产生的动物模型将使开发和测试副作用更小的特定药物成为可能。此外，我们的技术可用于识别人类疾病（如精神分裂症和帕金森病）小鼠模型中特定回路发生的变化，为这些疾病进展背后的机制提供线索。最后，目前无法监测特定受体亚型的激活也适用于其他受体家族。由于我们的系统是模块化的，它可以很容易地适应于研究其他受体。因此，在动物模型中选择性地监测特定受体激活的方法将对生物医学研究界的一个非常广泛的部分产生重大影响。我们提议产生一种新的分子方法来选择性地记录动物模型中特定多巴胺受体亚型的激活。多巴胺系统与多种疾病有关，如精神分裂症、双相情感障碍、注意缺陷多动障碍、妥瑞氏综合征、成瘾、帕金森病和高血压。这种动物模型的可用性将使开发和测试更特异性的多巴胺受体激动剂和拮抗剂具有更少的副作用。

Neurons communicate with one another by secreting chemical signals called neurotransmitters. The neurotransmitters secreted from one neuron bind specific receptors on the membranes of other cells and elicit a cascade of responses in these cells. Dopamine is a neurotransmitter that regulates a diverse array of biological processes including cognition and emotion, motivation and reward, locomotion, and the release of certain hormones. Imbalances in the dopamine system have been implicated in disorders as diverse as schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, Tourette's syndrome, addiction, Parkinson's disease, and hypertension. The mammalian genome encodes five different receptors for dopamine that can be grouped into two classes based on their cellular signaling and sequence homology. The various types of receptors are thought to mediate different biological functions and are implicated in different disorders. The two classes of dopamine receptors can also be distinguished pharmacologically, but this discrimination is not absolute. Furthermore, it is much more difficult to distinguish pharmacologically between receptors within the same class. A given drug often acts on multiple receptors, producing unwanted side effects. Thus, having highly specific drugs for the various dopamine receptors is critical for the successful treatment of a disorder that involves a particular dopamine receptor type with minimal side effects. Since many neurons express multiple types of dopamine receptors, it is currently impossible to attribute the effects of a particular drug to a specific receptor. Clinically, this gap of knowledge translates into an inability to predict and address the side effects of a given drug. Here we present a novel molecular method to selectively record activation of a particular dopamine receptor subtype in the murine brain. Since our system is extremely selective, it can be used to unequivocally determine which receptor subtype has been activated in a particular neuron in response to a given drug. This is accomplished regardless of the presence of other kinds of dopamine receptors in this neuron. The animal models that we will generate will enable the development and testing of specific drugs with fewer side effects. Moreover, our technology can be used to identify changes that occur in particular circuits in mouse models for human diseases such as schizophrenia and Parkinson's disease, providing clues regarding the mechanisms underlying the progression of these diseases. Finally, the current inability to monitor the activation of a particular receptor subtype also applies to other families of receptors. Since our system is modular, it can be readily adapted to study other receptors. A method to selectively monitor activation of specific receptors in an animal model will thus have a major impact on a very broad segment of the biomedical research community. We are proposing to generate a novel molecular method to selectively record the activation of a particular dopamine receptor subtype in an animal model. The dopamine system has been implicated in multiple disorders such as schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, Tourette's syndrome, addiction, Parkinson's disease and hypertension. The availability of such animal models will enable the development and testing of much more specific dopamine receptor agonists and antagonists with fewer side effects.