The role of phasic dopamine release in cue-evoked motivated behaviors

阶段性多巴胺释放在提示诱发的动机行为中的作用

• 批准号: 7806792
• 负责人: Matthew J. Wanat
• 金额: $ 5.01万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806792
• 关键词: Address; Affect; Attenuated; Behavior; Behavioral; Behavioral Paradigm; Cocaine; Cues; Disease; Dopamine; Drug Addiction; Drug Delivery Systems; Emotional; Event; Food; Food deprivation (experimental); Foundations; Goals; Infusion procedures; Length; Measures; Motivation; Nucleus Accumbens; Output; Pattern; Pharmaceutical Preparations; Psychological reinforcement; Punishment; Rattus; Reinforcement Schedule; Research; Rodent; Role; Satiation; Scanning; Signal Transduction; Societies; Withdrawal; addiction; cocaine exposure; dopamine system; dopaminergic neuron; drug craving; drug of abuse; economic impact; experience; feeding; food consumption; genetic manipulation; improved; motivated behavior; neural circuit; neurochemistry; neuromechanism; reinforcer

DESCRIPTION (provided by applicant): Drug addiction is a disease with a devastating emotional and economic impact on society, which in turn has stimulated research that seeks to identify the neural mechanisms involved with addiction. Many lines of evidence suggest that drug addiction alters the motivation to pursue drugs. In particular, drug-related cues can promote motivated drug seeking through activation of the mesocorticolimbic dopamine system. However, little is known regarding how reinforcer-associated cues affect dopamine release in the nucleus accumbens (NAcc) in behaviors specifically examining motivation. Identifying the role of dopamine release to cues associated with reinforcer availability during motivated behaviors will improve our understanding of the neurochemical signals involved with motivation, and will also highlight specific dopamine release patterns that when blocked, could potentially attenuate how drug-related cues promote drug seeking. Motivation is often assessed in operant tasks that utilize progressive ratio (PR) reinforcement schedules. During PR reinforcement schedules, the net value of the reinforcer is diminished as the operant requirement to obtain a reinforcer increases on subsequent trials until operant responding ceases, which is the 'break- point' and is a measure of motivational effort one will expend to obtain a reinforcer. While dopamine release in the NAcc is involved with motivated operant output, surprisingly little is known regarding the temporal release patterns of dopamine during motivated behaviors. Phasic (sub-second) dopamine release in the NAcc precedes the initiation of goal-directed actions, which suggests that phasic dopamine release is involved with motivated behaviors. However, it is unknown how dopamine is released to cues associated with reinforcer availability in behavioral paradigms explicitly assessing motivation. In this regard, this proposal addresses this experimental question by utilizing voltammetry to determine the role of phasic, sub- second dopamine release in the NAcc to cues predicting reinforcer availability in rats during an operant task with a PR reinforcement schedule for either natural reinforcers (Aim 1) or drugs of abuse (Aim 2). A critical component of drug addiction is an enhanced motivation to purse drugs, which involves the actions of dopamine, although it is unknown how dopamine is released during behaviors specifically examining motivation. This proposal examines the role of sub-second dopamine release in the motivated pursuit of both natural (food) and drug (cocaine) reinforcers, which will enhance our understanding of the neurochemical signals involved with motivated behaviors, and will also highlight specific dopamine release patterns that when blocked, could reduce the motivation to pursue drugs.

药物成瘾是一种对社会具有破坏性情感和经济影响的疾病，这反过来又刺激了旨在确定与成瘾有关的神经机制的研究。许多证据表明，吸毒成瘾改变了追求毒品的动机。特别是，药物相关的线索可以通过激活中皮质边缘多巴胺系统来促进有动机的药物寻求。然而，很少有人知道，在具体检查动机的行为中，与行为相关的线索如何影响多巴胺在丘脑核（NAcc）中的释放。确定多巴胺释放的作用，以提示与动机行为过程中的药物可用性将提高我们的理解与动机有关的神经化学信号，也将突出特定的多巴胺释放模式，当被阻止时，可能会削弱药物相关的线索如何促进药物寻求。 动机经常被评估在操作性任务，利用累进比率（PR）强化时间表。在PR强化计划期间，随着获得一个应答者的操作性要求在随后的试验中增加，应答者的净值减少，直到操作性反应停止，这是“断点”，是一个人为获得一个应答者而付出的动机努力的量度。虽然多巴胺的释放在NAcc参与动机操作性输出，令人惊讶的是，很少有人知道有关的时间释放模式的多巴胺在动机行为。NAcc中的阶段性（亚秒）多巴胺释放先于目标导向行为的启动，这表明阶段性多巴胺释放与动机行为有关。然而，目前还不清楚多巴胺是如何释放到与明确评估动机的行为范式中的可用性相关的线索中的。在这方面，该提议通过利用伏安法来确定NAcc中的阶段性亚秒多巴胺释放的作用以提示预测在具有天然多巴胺（目的1）或滥用药物（目的2）的PR强化时间表的操作性任务期间大鼠中多巴胺的可用性来解决该实验问题。 药物成瘾的一个关键组成部分是增强的购买药物的动机，这涉及多巴胺的作用，尽管目前尚不清楚多巴胺是如何在具体检查动机的行为中释放的。该提案研究了亚秒多巴胺释放在自然（食物）和药物（可卡因）刺激物的有动机追求中的作用，这将增强我们对与动机行为有关的神经化学信号的理解，也将突出特定的多巴胺释放模式，当被阻止时，可能会减少追求药物的动机。