Opioid Mechanisms that Facilitate Reward

在这个NIDA/NIH独立科学家奖的延续申请中，提出了一个研究项目，以阐明大鼠慢性食物限制增加药物奖励的内分泌和脑多巴胺机制。本实验室先前的研究表明，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，恢复自由进食或亚慢性脑室注射胰岛素一周后，这种增强可以逆转。在本应用的研究1中，研究人员进一步研究了食物限制大鼠的中枢胰岛素和瘦素水平持续低于正常水平，作为食物限制对药物奖励增强效应的可能触发因素。研究II探讨了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强药物奖励。研究III-VI探讨了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早期基因表达和/或信号转导。具体来说，研究III检测了单独和联合给药多巴胺受体类型选择性激动剂诱导的c-fos表达。研究IV通过测量喹匹罗刺激的[35S]GTPgammaS结合来检测D-2受体和g蛋白之间的功能偶联。研究V检测d -1激动剂诱导的腺苷酸环化酶的刺激。研究六检测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中发现的神经适应性是否可以通过恢复随意进食或亚慢性i.c.v.激素管理的相同方案逆转食物限制的行为影响。通过阐明内分泌肥胖激素、中枢神经传递和大脑奖赏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机体变量的理解，并有助于解释药物滥用和饮食失调的高合并症。

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.