Opioid Mechanisms that Facilitate Reward

在申请延续NIDA/NIH独立科学家奖的过程中，提出了一项研究计划，旨在阐明慢性食物限制增加大鼠药物奖励的内分泌和大脑多巴胺机制。该实验室以前的工作表明，慢性食物限制增强了对各种滥用药物的奖励、运动和细胞激活效应的中枢敏感性。初步结果表明，恢复一周的随意食物通路或亚慢性脑室内通路(i.c.v)可以逆转这种增强。注射胰岛素。在这项应用的研究I中，进一步研究了食物限制大鼠的中枢胰岛素和瘦素持续低于正常水平，作为食物限制对药物奖励增强效应的可能触发因素。第二项研究考察了D-3多巴胺受体的下调是否可能有助于通过限制食物来增加药物奖赏。研究III-VI研究慢性食物限制是否改变了调节药物奖赏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。具体地说，研究III检查了单独和联合应用多巴胺受体类型选择性激动剂诱导的c-fos表达。研究四通过测量喹比罗刺激的[35S]GTP-GammaS结合来检查D-2受体和G蛋白之间的功能偶联。研究V检测D-1激动剂对腺酰环化酶的刺激。研究VI检测苯丙胺诱导的细胞外信号调节激酶(ERK)的激活。最后，第七项研究试图确定研究III-VI中确定的神经适应是否被恢复自由进食或亚慢性I.C.V的相同方案逆转。能逆转限食行为影响的荷尔蒙管理。通过澄清内分泌脂肪激素、中枢神经传递和大脑奖励回路敏感性之间的关系，这项工作可能会提高我们对影响药物滥用易感性的组织变量的理解，并有助于解释药物滥用和饮食失调的高共患率。

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.