CNS Mechanisms that Modulate Reward

调节奖励的中枢神经系统机制

基本信息

批准号：
7213416
负责人：
Kenneth D Carr
金额：
$ 35.59万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1986
资助国家：
美国
起止时间：
1986-01-01 至 2008-06-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7213416
关键词：
Acute Adenylate Cyclase Adipose tissue Adrenal Cortex Hormones Affect Agonist Area Behavioral Binding Body Weight Brain Chronic Cocaine Comorbidity Corpus striatum structure Coupling Dextroamphetamine Dopamine Dopamine Agonists Dopamine Receptor Dorsal Dose Drug abuse Eating Disorders Endocrine Extracellular Signal Regulated Kinases FOS gene Food GTP Binding GTP-Binding Proteins Gene Expression Hormones Immunohistochemistry Individual Infusion procedures Insulin Investigation Laboratories Leptin Link Measures Mediating Midbrain structure Mitogen-Activated Protein Kinases Motor N-Methylaspartate Narcotic Antagonists Neuropeptides Nucleus Accumbens Obesity Opioid Pharmaceutical Preparations Phencyclidine Prosencephalon Quinpirole Rattus Recovery Research Rewards Role Self Administration Signal Transduction Signal Transduction Pathway Structure Time Treatment Protocols Work day drug of abuse drug reward extracellular feeding food restriction improved melanocortin receptor neuroadaptation neurotransmission postsynaptic psychostimulant putamen receptor receptor function response reward circuitry

项目摘要

DESCRIPTION (provided by applicant): Previous work in this laboratory indicates that chronic food restriction enhances central sensitivity to the rewarding, motor- and cellular-activating effects of diverse drugs of abuse and direct dopamine receptor agonists. Moreover, the behavioral augmenting effect of food restriction is reversed by 7-12 days of restored ad libitum feeding and recovery of body weight. In Study I of this application, the sustained subnormal levels of insulin and leptin that characterize the food-restricted rat are investigated as possible triggers by determining whether continuous intracerebroventricular infusion of "replacement" hormone reverses the augmenting effect of food restriction on drug reward and motor activation. Studies II-V 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 II examines c-fos expression induced by individual and combined administration of dopamine receptor type-selective agonists. Study III examines functional coupling between D-2 dopamine receptors and G-protein by measuring quinpirole-stimulated [35S]GTPgS binding. Study IV examines D-1 dopamine agonist-induced stimulation of adenylyl cyclase. Study V examines d-amphetamine-induced activation of extracellular signal-regulated kinase (ERK). Finally, Study VI seeks to establish whether the neuroadaptations identified in Studies II-V 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.

描述（由申请人提供）：该实验室先前的工作表明，长期食物限制增强了中枢对各种滥用药物和直接多巴胺受体激动剂的奖励、运动和细胞激活作用的敏感性。此外，恢复随意进食和体重恢复7-12天可以逆转食物限制的行为增强效应。在本申请的研究 I 中，通过确定连续脑室内输注“替代”激素是否逆转食物限制对药物奖赏和运动的增强作用，将限制食物大鼠的胰岛素和瘦素水平持续低于正常水平作为可能的触发因素进行了研究。激活。研究II-V调查长期食物限制是否会改变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早期基因表达和/或信号转导。具体来说，研究 II 检查了单独和联合施用多巴胺受体类型选择性激动剂诱导的 c-fos 表达。研究 III 通过测量喹吡罗刺激的 [35S]GTPgS 结合来检查 D-2 多巴胺受体和 G 蛋白之间的功能耦合。研究 IV 检查 D-1 多巴胺激动剂诱导的腺苷酸环化酶刺激。研究 V 检查 d-苯丙胺诱导的细胞外信号调节激酶 (ERK) 激活。最后，研究 VI 试图确定研究 II-V 中确定的神经适应是否可以通过恢复随意喂养或亚慢性静脉注射、激素施用等相同方案来逆转，从而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脆弱性的有机变量的理解，并有助于解释药物滥用和饮食失调的高共病率。