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

描述(申请人提供)：味觉指导了很多饮食行为。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的贡献，包括饮食，是毋庸置疑的，有一系列与多巴胺有关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的环路上，但多巴胺能机制也位于后脑，外周味觉神经传入的后脑。先前的报告已经证明，全身给予穿过血脑屏障的多巴胺D2受体拮抗剂可以减少大鼠由享乐驱动的蔗糖摄入量，而R03提案中提出的初步数据显示，当D2受体拮抗剂拉氯普利第四次脑室注射(4icv)时，这一点得到了概括，这是一项广泛但仅针对后脑区的技术。然而，尽管味觉信号具有享乐性，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，现在就断定多巴胺能调制只影响味觉奖励还为时过早，因为感知到的味觉信号强度的降低也可能导致情感潜力的降低。这里提出的进一步的初步发现提供了证据，即4icv拉氯必利输注降低了大鼠对蔗糖的检测能力，这是在使用专门的Gustometer进行的基于操作性条件的信号检测任务中评估的。这些数据表明，在大鼠模型中，后脑D2受体拮抗直接和/或间接地在基本感觉水平上降低了蔗糖味觉的敏感性。R03申请中提出的实验的目标是扩展这些有希望的初步数据，并使用专门处理味觉和情感方面的行为任务来评估后脑中多巴胺D2受体的功能必要性。具体地说，这些实验将评估4icv拉氯必利输注引起的享乐驱动的摄入结果是如何在行为上实现的，以及通过探索影响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，将指导进一步的机械性实验，包括那些使用针对特定大脑区域的选择性实质输注的实验。这些未来的研究将作为R01提案的基础，在该提案中可以使用进一步的多学科方法。总体而言，这项R03申请中提出的研究将从多巴胺开始，开始解开正常和紊乱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.