OPIOID MECHANISMS THAT FACILITATE REWARD

描述：(申请人摘要) 在NIDA-NIH独立科学家奖(ISA)的这份申请中，a 提出了一项研究计划，以阐明大脑阿片类药物的机制 在长期限食期间促进奖励。一个多学科的 解决这个问题的方法是有计划的，它利用了最近开发的 分子生物学方法论。 先前的研究表明，新陈代谢需要状态会激活大脑 使动物对电的奖赏效应敏感的阿片类机制 大脑刺激。Mu和Kappa阿片类药物参与的证据 受体和强啡肽A已经被获得。《研究I》 和II血浆皮质酮和胰岛素的变化与 新陈代谢需求将作为奖励的可能触发因素进行调查 敏化。研究III和IV遵循的是观察到的食物限制 产生脑区强啡肽水平以及MU和Kappa值的变化 受体结合。溶液杂交和原位杂交 将使用组织化学来阐明这些变化通过寻求 相应的受体和前强啡肽基因转录的变化。在……里面 研究V[35S]GTP-Gamma放射自显影将用于研究 G蛋白活化变化的神经解剖学分布。因为食物 限制似乎伴随着阿片肽的紧张性增加 释放，c-fos免疫组织化学将在研究VI中识别 脑部对纳曲酮的反应表现出“反弹”激活的区域。 研究七将利用微量注射拮抗剂、反义 寡脱氧核苷酸和阿片肽抗体用于鉴定 脑区(S)和内源性多肽-受体类型组合 调节奖赏的敏感化。 除了支持一项研究计划外，ISA还将提供PI 有机会接受分子生物学方法方面的培训 加大行为神经科学调查力度。这 培训，将通过与几个同事合作的方式进行， 将增强PI带来现代神经科学方法的能力 关注与激励有关的基本行为问题的解决 和奖励。在ISA支持期间，助理PL 博士后培训项目主任，将担任 受训人员以及住院医生和酒精中毒和酒精科研究员 滥用药物。对国际和平协会的长期支持和承诺 由ISA催生的科学发展将确保 提高了实验室的生产率，从而改善了 研究训练。

DESCRIPTION: (Applicant's Abstract) In this application for an NIDA-NIH Independent Scientist Award (ISA) a program of research is proposed to elucidate brain opioid mechanisms that facilitate reward during chronic food restriction. A multidisciplinary approach to this problem is planned which exploits recently developed molecular biological methodologies. Previous research indicates that metabolic need states activate a brain opioid mechanism that sensitizes animals to rewarding effects of electrical brain stimulation. Evidence for the involvement of mu and kappa opioid receptors along with dynorphin A peptides has been obtained. In Studies I and II the changes in plasma corticosterone and insulin associated with metabolic need will be investigated as possible triggers of reward sensitization. Studies III and IV follow observations that food restriction produces brain regional changes in dynorphin peptide levels and mu and kappa receptor binding. Solution hybridization and in situ hybridization histochemistry will be used to elucidate these changes by seeking corresponding changes in receptor and prodynorphin gene transcription. In Study V [35S]GTP-gammaS autoradiography will be used to investigate the neuroanatomical distribution of changes in G-protein activation. Since food restriction appears to be accompanied by a tonic increase in opioid peptide release, c-fos immunohistochemistry will be used in Study VI to identify brain regions that display 'rebound' activation in response to naltrexone. Study VII will utilize microinjections of antagonists, antisense oligodeoxynucleotides and antibodies to opioid peptides to identify the brain region(s) and intrinsic peptide-receptor type combinations that mediate the sensitization of reward. In addition to supporting a research program, the ISA will provide the PI with opportunities for training in molecular biological approaches that increase the power of behavioral neuroscientific investigation. This training, which will occur by way of collaboration with several colleagues, will enhance the ability of the PI to bring modern neuroscientific methods to bear on the solution of basic behavioral problems relating to motivation and reward. During the period of ISA support, the Pl, who is Associate Director of the Postdoctoral Training Program, will serve as mentor to trainees as well as residents and fellows in the Division of Alcoholism and Substance Abuse. The long-term support and commitment to the PI's scientific development engendered by the ISA will ensure the stability and productivity of the laboratory, thereby creating an improved setting for research training.