OPIOID SYSTEMS IN VENTRAL STRIATUM AND FOOD REWARD

腹侧纹状体中的阿片类药物系统和食物奖励

• 批准号: 2122458
• 负责人: Ann E. Kelley
• 金额: $ 11.63万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-03-15 至 1998-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2122458
• 关键词: behavior test; behavioral habituation /sensitization; brain mapping; dopamine antagonists; dopamine receptor; endogenous opioid; laboratory rat; microinjections; morphine; motivation; neuropharmacology; nucleus accumbens; nutrient intake activity; operant conditionings; opioid receptor; psychopharmacology; receptor expression; reinforcer; sweetening agents

Opiates, such as heroin and morphine, constitute one of the major classes of abused drugs in the world. Although the treatment of opiate addiction remains problematic, enormous advances have been made in our general understanding of the systems on which these drugs act in the brain. The endogenous opioids are believed to play a major role in diverse biological processes such as pain modulation, affect and emotion, response to stress, and reinforcement. One major area of research has focused on opioid mediation of feeding and drinking. A hypothesis that has received considerable support states that opioids specifically regulate the rewarding or hedonic aspects of food. Moreover, clinical findings suggest that dysfunction of opioids may in some way be linked to human disorders characterized by excessive cravings, impulsive behavior and loss of control, much as in bulimia and alcoholism. In the past several years, our laboratory has investigated the effects of opioid manipulations of the nucleus accumbens on feeding behavior. This brain structure, part of the ventral striatum, is thought to be a critical substrate for the reinforcing effects of opiate and psychostimulant drugs. Our research to date has shown that microinjection of morphine into the nucleus accumbens results in a striking increase in feeding behavior and excessive food intake. This effect has been shown to be primarily mu-receptor mediated and anatomically localized to ventral, limbic-afferented striatal regions. Moreover, conditioned feeding develops following control or sham injections in animals that have received repeated microinjections of morphine. Injection of an opiate antagonist into this region reduces consumption of a sucrose solution. This project aims to further explore these findings and to test the hypothesis that opioid systems in the ventral striatum may be particularly involved in the hedonic and associative mechanisms underlying ingestive behavior. Our three specific objectives are: (i) To conduct a pharmacological analysis of the role of specific opiate receptor subtypes within the nucleus accumbens and other striatal sites in the rewarding effects of a highly palatable saccharin solution. (ii) To carry out a behavioral analysis of the motivational state induced by opioid manipulation of the nucleus accumbens. Several behavioral paradigms will be utilized including responding for sweet reward on a progressive ratio schedule, conditioned reinforcement, discrete-trial learning in a T-maze, and diet selection in rats previously selected for specific patterns of baseline diet preferences. (iii) To analyze the development and expression of the conditioned feeding response that results from repeated exposure of the nucleus accumbens to opiates. The approach common to all these experiments is the utilization of direct brain microinjection of opioid agonists and antagonists in conjunction with specific behavioral paradigms. The outcome of these experiments may contribute to our understanding of the ventral striatum in brain reinforcement processes.

阿片类药物，如海洛因和吗啡，构成主要类别之一， 滥用药物的国家虽然鸦片成瘾的治疗 仍然存在问题，但我们的总体工作取得了巨大进展， 了解这些药物在大脑中作用的系统。的 内源性阿片样物质被认为在多种生物学过程中起主要作用， 过程如疼痛调节，影响和情绪，对压力的反应， 和加强。一个主要的研究领域集中在阿片类药物 调解进食和饮水。一个假设， 大量的支持指出，阿片类药物专门调节 食物的奖励或享乐方面。此外，临床研究结果表明， 阿片类药物的功能障碍可能与人类疾病有关， 以过度渴望、冲动行为和丧失 控制，就像在暴食症和酗酒。在过去的几年里，我们 实验室已经研究了阿片类药物操作对 丘脑核对摄食行为的影响这个大脑结构， 腹侧纹状体，被认为是一个关键的基板， 鸦片和精神兴奋剂的强化作用。我们的研究 有资料表明，向延髓核内微量注射吗啡 导致进食行为和过量食物的显著增加 摄入这种作用已被证明主要是μ受体介导的。 并且解剖学上定位于腹侧、边缘传入纹状体区域。 此外，在对照组或假手术组之后， 在接受重复微量注射的动物中注射 吗啡向该区域注射阿片拮抗剂可减少 消耗蔗糖溶液。该项目旨在进一步探索 这些发现和测试的假设，阿片类药物系统在 腹侧纹状体可能特别参与享乐和 摄食行为背后的关联机制我们的三个具体 目的是：（一）进行药理学分析的作用， 特定的阿片受体亚型内的核和其他 一种非常可口的糖精的奖励效应中的纹状体部位 溶液(ii)为了对动机进行行为分析， 阿片类药物操纵延髓核引起的状态。几 将利用行为范例，包括对甜的反应， 按累进比例奖励，条件强化， 在T-迷宫中的离散试验学习，以及大鼠先前的饮食选择 根据基线饮食偏好的特定模式进行选择。(iii)到 分析条件性摄食反应的发生和表达 这是由于重复暴露于阿片类药物的神经核。 所有这些实验的共同方法是利用直接 联合脑微量注射阿片类激动剂和拮抗剂 特定的行为模式。这些实验的结果可能 有助于我们对脑腹侧纹状体的了解 强化过程。