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

描述（由申请人提供）：味觉在很大程度上指导着饮食行为。当味觉改变时，营养状况和生活质量通常会受到负面影响，但介导这些味觉变化的神经化学和电路仍有待确定。多巴胺对动机和奖励驱动行为的贡献，包括饮食，是无可争议的，并且有一系列涉及多巴胺的精神病理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回路中，但多巴胺能机制也位于外周味觉神经传入的后脑。先前的报告已经证明，通过血脑屏障的多巴胺D2受体拮抗剂的全身管理可以减少大鼠的享乐性驱动的蔗糖摄入量，并且在R03提案中提出的初步数据表明，当D2受体拮抗剂raclopride注入第4脑室内（4icv）时，这种技术可以广泛但专门针对后脑区域。然而，尽管味觉信号具有享乐价，这与它们无条件促进或阻止液体摄入的能力有关，但它们必须首先被检测到。因此，多巴胺能调节仅影响味觉奖励的结论还为时过早，因为感知感官味觉信号强度的降低也可能导致情感效力的降低。本文提出的进一步初步研究结果提供了证据，证明4icv的氯氯pride输注降低了大鼠对蔗糖的可检测性，这是使用专门的量计评估的操作性条件信号检测任务。这些数据表明，在大鼠模型中，后脑D2受体拮抗剂在基本感觉水平上直接和/或间接地降低了蔗糖味觉敏感性。本R03应用程序中提出的实验目标是扩展这些有希望的初步数据，并通过具体处理味觉的感觉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。具体来说，实验将通过探索化学特异性，评估4icv盐酸氯pride输注诱导的享乐驱动摄入结果是如何在行为上实现的，以及D2受体阻断对感官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来靶向特定脑区域的实验。这些未来的研究将作为R01提案的基础，其中可以使用进一步的多学科方法。总的来说，在这个R03申请中提出的研究将开始揭示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.