Striatal Acetylcholine-Opioid Interactions and Feeding

描述(申请人提供)：目前肥胖的“流行病”是一个日益严重的问题，在世界各地的社会。寻找长期治疗是一个持续的过程，到目前为止主要关注动态平衡因素，特别是在下丘脑。这项拟议的研究旨在解决纹状体乙酰胆碱系统和阿片系统之间在食物摄入量方面可能存在的相互作用。我们的初步结果表明，纹状体内输注毒扁豆碱拮抗剂东莨菪碱可长期减少食物摄入量，并使阿片类药物诱导的摄食反应脱敏。在目前的提案中，我们将探讨东莨菪碱治疗对各种行为和神经药理学参数的影响。将进行一项时程研究，以确定东莨菪碱厌食的持续时间，进一步的实验将检测东莨菪碱在不同动机状态下诱导的变化以及对其他纹状体神经递质系统的调节。除了这些实验外，还将进行纹状体东莨菪碱清除的药代动力学研究，同时还将进行神经药理学分析，以评估纹状体内阿片受体的功能。与公共卫生的相关性：本提案中概述的工作有可能确定控制喂养的一种新的神经药理学途径。这可能会导致控制食欲的新药，这可能有助于缓解肥胖症的流行。

DESCRIPTION (provided by applicant): The current "epidemic" of obesity is an increasing problem in societies world wide. The search for a long term treatment is an ongoing process with much focus to date on homeostatic factors, particularly in the hypothalamus. The proposed research is designed to address a possible interaction between the striatal acetylcholine system and opioid system with regard to food intake. Our preliminary results indicate that intrastriatal infusions of the muscarinic antagonist scopolamine produce a long-term reduction on food intake and a desensitization of opioid-induced feeding responses. In the current proposal, we will explore various behavioral and neuropharmacological parameters affected by scopolamine treatment. A time course study will be conducted to determine the duration of scopolamine anorexia and further experiments will examine scopolamine-induced alterations in different motivational states and modulation of other striatal neurotransmitter systems. In addition to these experiments, a pharmacokinetic study of scopolamine clearance from striatum will be performed along with neuropharmacological assays to assess the function of the opioid receptor inside the striatum. Relevance to public health: The work outlined in this proposal has the potential to identify a novel neuropharmacological pathway in the control of feeding. This could lead to new drugs for appetitive control, which could help alleviate the obesity epidemic.