Opioid and Glutamate Modulation of Reward Value During Goal-Directed Behavior

描述(由申请者提供)：吸毒成瘾是一种慢性、复发性障碍，其特征是动机行为管理不善。要形成合理有效的成瘾药物疗法，就必须了解奖赏享乐症的神经生物学基础和奖赏价值的表现。以前的研究表明，内源性阿片系统是奖赏情感特性的潜在中介。此外，内源性阿片类药物已被证明可以调节大脑奖励回路中的谷氨酸传输。有趣的是，这些基底前脑区域的谷氨酸传输与动机行为密切相关，特别是对滥用物质的动机行为。因此，本提案的具体目的是使用一种新的工具范式来区分内源性阿片系统在消耗性快感、奖赏价值表征和一般动机唤醒中的作用，该工具范式专门设计用于区分目标导向行为的这些组成部分。我们还将阐明调节奖赏快感和奖赏价值表征的基础解剖基础，并验证内源性阿片类药物通过改变这些结构中谷氨酸释放来调节奖赏价值表征的假设。这些目标将通过使用内源性Li阿片受体系统的中央和外围操纵以及电酶过氧化聚吡咯和谷氨酸氧化酶包裹的铂微阵列生物传感器来实现，该生物传感器用于实时记录异质蔗糖寻找-摄取链期间的突触外谷氨酸，并进行完善的口感分析。已经确定，在这个链条的寻找部分上的表现反映了报酬的特定价值。因此，这些数据将阐明阿片类药物和谷氨酸能对奖赏快感的调节以及价值的编码。这项研究提案的长期目标是了解阿片系统如何调节奖励价值和动机。这项工作将为理解成瘾行为中内源性奖赏过程是如何出错的提供基础。内源性阿片和谷氨酸系统与几类滥用物质的增强和成瘾特性有关。我们打算了解这些系统是如何调节奖励处理的特定组成部分的。因此，这项研究不仅将使我们了解成瘾药物如何篡夺奖赏系统，还将为潜在药物疗法的研究提供信息。

DESCRIPTION (provided by applicant): Drug addiction is a chronic, relapsing disorder characterized by poorly managed motivated behavior. The formation of rational and effective pharmacotherapies for addictions necessitates an understanding of the neurobiological underpinnings of reward hedonia and the representation of reward value. Previous research has implicated the endogenous opioid systems as a potential mediator of the affective properties of reward. Moreover, endogenous opioids have been shown to modulate glutamate transmission in the brain reward circuitry. Interestingly, glutamate transmission in these basal forebrain regions is highly implicated in motivated behavior, particularly towards abused substances. Therefore the specific aims of this proposal are to differentiate the role of the endogenous opioid systems in consummatory hedonia, reward value representation and general motivational arousal using a novel instrumental paradigm designed specifically to distinguish these components of goal-directed actions. We will also elucidate the anatomical substrates within basal forebrain curcuitry regulating reward hedonia/and or the representation of reward value, and test the hypothesis that endogenous opioids modulate reward value representation through changes in glutamate release in these structures. These aims will be accomplished by using central and peripheral manipulation of the endogenous LI opioid receptor system as well as electroenzymatic overoxidized polypyrrole and glutamate oxidase-coated platinum micro-array biosensors for real-time recordings of extrasynaptic glutamate during a heterogeneous sucrose seeking-taking chain with a consummatory palatibility analyssi. It has been established that performance on the seeking component of this chain reflects the reward's specific value. Therefore, these data will elucidate the opioid and glutamatergic modulation ofreward hedonia and the encoding of value. It is the long-term objective of this research proposal to gain an understanding of how the opioid system regulates reward value and motivation. This work will provide a basis for comprehending how the endogenous reward processes go awry during addictive behavior. The endogenous opioid and glutamate systems are implicated in the reinforcing and addictive properties of several classes of abused substances. We intend to understand how these systems mediate specific components of reward processing. Consequently, this research will inform not only our understanding of how the reward systems may be usurped by addictive drugs, but also research on potential pharmacotherapies.