Central Dopaminergic Modulation of Sensory and Reward Taste Function in Rats.

描述（由申请人提供）：味觉引导大部分饮食行为。当味觉改变时，营养状况和生活质量往往会受到负面影响，但调节这些味觉变化的神经化学和回路仍有待确定。多巴胺对动机和奖励驱动的行为（包括饮食）的贡献是无可争议的，并且患有一系列与多巴胺有关的精神病理学的患者报告了味觉障碍。关于多巴胺在味觉引导行为中的作用的研究主要集中在前脑中的回路上，但是多巴胺能机制也位于外周味觉神经传入的后脑中。先前的报告已经证明，全身给予多巴胺D2受体拮抗剂，穿过血脑屏障，减少大鼠的享乐驱动的蔗糖摄入量，并且本R 03提案中提供的初步数据表明，当第四次脑室内（4 icv）输注雷氯必利（一种D2受体拮抗剂）时，这一点得到了概括，该技术广泛但专门针对后脑区域。然而，尽管味觉信号具有与它们无条件地促进或阻止流体摄入的能力相关的享乐价，但它们必须首先被检测到。因此，这是为时过早的结论，多巴胺能调节只影响味觉奖励，因为在感知的感官味觉信号的强度降低也可能导致降低的情感效力。进一步的初步研究结果提供的证据表明，4 icv雷氯必利输注降低了蔗糖的检测能力的大鼠在一个操作性条件反射为基础的信号检测任务，使用专门的味觉计评估。这些数据表明，在大鼠模型中，后脑D2受体拮抗作用直接和/或间接降低了基本感觉水平的蔗糖味觉敏感性。在R 03申请中提出的实验的目标是扩展这些有希望的初步数据，并使用专门针对味觉的感官和情感方面的行为任务来评估多巴胺D2受体在后脑中的功能必要性。具体而言，实验将评估如何在行为上实现由4 icv雷氯必利输注诱导的享乐驱动的摄入结果，以及通过探索效应的化学特异性来评估D2受体阻断对感觉味觉功能的影响程度。这些功能研究的结果，以及初步的免疫组织化学评估，将指导进一步的机制实验，包括那些使用选择性脑实质输注靶向特定脑区。这些未来的研究将作为R 01提案的基础，其中可以使用进一步的多学科方法。总的来说，R 03申请中提出的研究将开始解开从多巴胺开始的正常和紊乱的味觉引导行为所涉及的神经化学。

DESCRIPTION (provided by applicant): The sense of taste guides much of eating and drinking behavior. Nutritional status and quality of life are often negatively impacted when taste perception is altered, but the neurochemistry and circuitry mediating these taste changes remains to be determined. The contribution of dopamine to motivated and reward-driven behavior, including eating and drinking, is uncontested, and taste disturbances are reported by patients with an array of psychopathologies in which dopamine is implicated. Studies concerning the role of dopamine in taste- guided behavior have focused primarily on circuits in the forebrain, but dopaminergic machinery is also located in the hindbrain where peripheral taste nerves afferent. Prior reports have demonstrated that systemic administration of dopamine D2 receptor antagonists that cross the blood-brain barrier reduce hedonically driven sucrose intake by rats, and the preliminary data presented in this R03 proposal show that this is recapitulated when raclopride, a D2 receptor antagonist, is infused 4th intracerebroventricularly (4icv), a technique that broadly, but exclusively, targets hindbrain areas. However, although taste signals have hedonic valence that is related to their ability to unconditionally promote or discourage intake of fluids, they must first be detected. Thus, it is premature to conclude that dopaminergic modulation impacts only taste reward since a decrease in the strength of the perceived sensory taste signal may also result in decreased affective potency. Further preliminary findings presented here provide evidence that 4icv raclopride infusion decreases the detectability of sucrose by rats as assessed in an operant conditioning-based signal detection task using a specialized gustometer. These data suggest that hindbrain D2 receptor antagonism directly and/or indirectly decreases sucrose taste sensitivity at a basic sensory level in a rat model. The goal of the experiments proposed in this R03 application is to expand upon these promising preliminary data and evaluate the functional necessity of dopamine D2 receptors in the hindbrain using behavioral tasks that specifically address the sensory and affective aspects of taste. Specifically, the experiments will assess how the hedonically driven intake outcomes induced by 4icv raclopride infusion are behaviorally achieved and the extent to which D2 receptor blockade impinges on sensory taste function by exploring the chemo specificity of the effects. The outcomes of these functional studies, as well as an initial immunohistochemical assessment, will guide further mechanistic experiments, including those using selective parenchymal infusions that target specific brain areas. These future studies will serve as the foundation for an R01 proposal in which further multidisciplinary approaches can be used. Overall, the research proposed in this R03 application will begin to unravel the neurochemistry involved in normal and disordered taste-guided behavior starting with dopamine.