CNS Mechanisms that Modulate Reward

调节奖励的中枢神经系统机制

• 批准号: 7651779
• 负责人: Kenneth D Carr
• 金额: $ 42.28万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-01-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7651779
• 关键词: AMPA Receptors; Address; Animal Model; Behavior; Behavioral; Binge Eating; Biochemical; Body Weight; Body Weight decreased; Brain-Derived Neurotrophic Factor; CREB1 gene; Calcium/calmodulin-dependent protein kinase; Chronic; Clinical; Comorbidity; Corpus striatum structure; Coupled; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Dextroamphetamine; Dopamine; Dopamine Agonists; Dopamine Receptor; Dose; Drug abuse; Eating Disorders; Exercise; FOS gene; Food; Gene Expression; Glutamate Receptor; Goals; Immunohistochemistry; Infusion procedures; Investigation; K 252a; Laboratory Study; Learning; MAP Kinase Gene; MEKs; Maintenance; Mediating; Microinjections; Midbrain structure; Mitogen Activated Protein Kinase 1; Molecular; Motor; N-Methyl-D-Aspartate Receptors; NR1 NMDA receptor; Neurons; Neuropeptide Gene; Obsessive compulsive behavior; Pathway interactions; Pattern; Pharmaceutical Preparations; Phase; Phosphorylation; Phosphotransferases; Physiological; Population; Prosencephalon; Rattus; Receptor Protein-Tyrosine Kinases; Regulation; Relative (related person); Research; Rewards; Rodent; Secondary to; Signal Transduction; Site; Stress; Testing; Up-Regulation; Ventral Tegmental Area; Western Blotting; Work; behavior measurement; calmodulin-dependent protein kinase II; density; dopamine transporter; drug of abuse; drug reward; energy balance; feeding; follow-up; food restriction; inhibitor/antagonist; interest; neuroadaptation; novel; postsynaptic; preclinical study; preference; putamen; research study; response

DESCRIPTION (provided by applicant): Chronic food restriction (FR) increases behavioral sensitivity to drugs of abuse in animal models and is associated with binge eating, which shares comorbidity with drug abuse, in clinical populations. Previous behavioral, biochemical and molecular studies of this laboratory suggest that FR increases the rewarding and locomotor-activating effects of abused drugs as a result of striatal neuroadaptations. Increases in cell signaling and gene expression in response to d- amphetamine and D-1 dopamine (DA) receptor stimulation have been observed. Of particular interest are increased phosphorylation of the NMDA receptor NR1 subunit, AMPA receptor GluR1 subunit, and upregulation of NMDA receptor-dependent ERK 1/2 MAP kinase and CaM kinase II signaling, CREB phosphorylation, and c-fos and neuropeptide gene expression. Several findings have been obtained that support a schema in which the striatal neuroadaptations are secondary to a decrease in basal DA. Moreover, recent findings suggest that decreased stimulation of one or more receptor tyrosine kinases, -most clearly, TrkB-, in the ventral tegmental area (VTA) may be a triggering condition for the striatal and behavioral effects of FR. While the neuroadaptations under investigation may adaptively invigorate goal-directed behavior and facilitate reward-related learning during periods of persistent negative energy balance, they may also be vulnerable to subversion by drugs of abuse and palatable foods in a manner that reinforces maladaptive compulsive behavior. The research proposed in this application is aimed at elucidating midbrain and striatal mechanisms involved in the increased behavioral responsiveness of FR rats to drugs of abuse. Chronic food restriction increases behavioral sensitivity to drugs of abuse in animal models and is associated with binge eating, compulsive exercise, and comorbid drug abuse with eating disorders in clinical populations. The proposed preclinical studies will investigate whether changes in trophic factor regulation of midbrain dopamine neuronal function and consequent alterations in interrelated dopamine and glutamate receptor mechanisms in reward-related forebrain regions are involved in the enhanced behavioral sensitivity of food-restricted subjects to drugs of abuse. This work may identify neuroadaptations that normally mediate adaptive changes in behavior during periods of food scarcity but also, under certain circumstances, increase vulnerability to maladaptive forms of goal-directed behavior, including drug abuse.

描述（由申请人提供）：长期食物限制（FR）会增加动物模型中对滥用药物的行为敏感性，并与临床人群中的暴饮暴食有关，暴食与药物滥用有共同的共病。该实验室之前的行为、生化和分子研究表明，由于纹状体神经适应，FR 增加了滥用药物的奖励和运动激活作用。已观察到响应 d-苯丙胺和 D-1 多巴胺 (DA) 受体刺激的细胞信号传导和基因表达增加。特别令人感兴趣的是 NMDA 受体 NR1 亚基、AMPA 受体 GluR1 亚基的磷酸化增加，以及 NMDA 受体依赖性 ERK 1/2 MAP 激酶和 CaM 激酶 II 信号传导、CREB ​​磷酸化以及 c-fos 和神经肽基因表达的上调。一些研究结果支持纹状体神经适应继发于基础 DA 减少的模式。此外，最近的研究结果表明，腹侧被盖区 (VTA) 中一种或多种受体酪氨酸激酶（最明显的是 TrkB）的刺激减少可能是 FR 纹状体和行为影响的触发条件。虽然正在研究的神经适应可能会在持续负能量平衡期间适应性地激发目标导向的行为并促进与奖励相关的学习，但它们也可能容易受到滥用药物和美味食物的颠覆，从而强化适应不良的强迫行为。本申请中提出的研究旨在阐明 FR 大鼠对滥用药物的行为反应性增加所涉及的中脑和纹状体机制。长期食物限制会增加动物模型中对滥用药物的行为敏感性，并与临床人群中的暴饮暴食、强迫性运动以及与饮食失调共存的药物滥用有关。拟议的临床前研究将调查中脑多巴胺神经元功能的营养因子调节的变化以及随后奖励相关前脑区域中相关的多巴胺和谷氨酸受体机制的改变是否与食物限制受试者对滥用药物的行为敏感性增强有关。这项工作可能会识别出通常在食物短缺期间介导行为适应性变化的神经适应，但在某些情况下，也会增加对目标导向行为（包括药物滥用）的适应不良形式的脆弱性。