Opioid Mechanisms that Facilitate Reward

在NIDA/NIH独立科学家奖的延续申请中，提出了一项研究计划，旨在阐明大鼠慢性限食增加药物奖励的内分泌和脑多巴胺机制。本实验室先前的工作表明，慢性食物限制增强了中枢对各种滥用药物的奖励、运动和细胞激活效应的敏感性。初步结果表明，增强被逆转一周恢复随意食物获取或亚慢性脑室内（i. c. v.）注射胰岛素在本申请的研究I中，进一步研究了作为食物限制大鼠特征的中枢胰岛素和瘦素的持续低于正常水平作为食物限制对药物奖励的增强作用的可能触发因素。研究二探讨是否下调的D-3多巴胺受体可以合理地有助于增加药物奖励的食物限制。研究III-VI调查慢性食物限制是否会改变调节药物奖励的边缘前脑结构中多种多巴胺受体类型介导的即刻早期基因表达和/或信号转导。具体而言，研究III检查c-fos表达诱导的多巴胺受体类型选择性激动剂的单独和联合给药。研究IV通过测量喹吡罗刺激的[35 S] GTP γ S结合来检查D-2受体和G蛋白之间的功能偶联。研究V检查D-1激动剂诱导的腺苷酸环化酶刺激。研究VI检查安非他明诱导的细胞外信号调节激酶（ERK）的激活。最后，研究VII试图确定研究III-VI中确定的神经适应是否被恢复随意喂养或亚慢性i. c. v.激素给药的相同方案逆转，这些方案逆转了食物限制的行为影响。通过澄清内分泌肥胖激素，中枢神经传递和大脑奖赏回路的敏感性之间的关系，这项工作可能会提高我们对影响药物滥用脆弱性的器官变量的理解，并有助于解释药物滥用和饮食失调的高共患病率。

In this application for continuation of a NIDA/NIH Independent Scientist Award, a program of research is proposed to elucidate endocrine and brain dopamine mechanisms that underlie the augmentation of drug reward by chronic food restriction in rats. Previous work in this laboratory indicates that chronic food restriction enhances central sensitivity to the rewarding, locomotor- and cellular- activating effects of diverse drugs of abuse. Preliminary results indicate that the augmentation is reversed by one week of restored ad libitum food access or subchronic intracerebroventricular (i.c.v.) insulin injection. In Study I of this application, the sustained subnormal levels of central insulin and leptin that characterize the food-restricted rat are further investigated as possible triggers of the augmenting effect of food restriction on drug reward. Study II examines whether downregulation of the D-3 dopamine receptor could plausibly contribute to the augmentation of drug reward by food restriction. Studies III-VI investigate whether chronic food restriction alters immediate early gene expression and/or signal transduction mediated by multiple dopamine receptor types in limbic forebrain structures that regulate drug reward. Specifically, Study III examines c-fos expression induced by individual and combined administration of dopamine receptor type-selective agonists. Study IV examines functional coupling between D-2 receptors and G-protein by measuring quinpirole- stimulated [35S]GTPgammaS binding. Study V examines D-1-agonist- induced stimulation of adenylyl cyclase. Study VI examines amphetamine-induced activation of extracellular signal-regulated kinase (ERK). Finally, Study VII seeks to establish whether the neuroadaptations identified in Studies III-VI are reversed by the same regimens of restored ad libitum feeding or subchronic i.c.v. hormone administration that reverse the behavioral effects of food restriction. By clarifying the relationship between endocrine adiposity hormones, central neurotransmission, and sensitivity of brain reward circuitry, this work may improve our understanding of organismic variables that affect vulnerability to drug abuse and help explain the high comorbidity of drug abuse and eating disorders.