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

描述(由申请者提供)：毒瘾是一种对社会具有破坏性的情感和经济影响的疾病，这反过来又刺激了试图确定与成瘾有关的神经机制的研究。许多证据表明，毒瘾会改变人们追求毒品的动机。特别是，与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动机的药物寻找。然而，关于增强剂相关的线索如何影响伏隔核(NAcc)中专门检查动机的行为中的多巴胺释放，人们知之甚少。识别多巴胺释放对动机行为中与增强剂可获得性相关的线索的作用将提高我们对与动机有关的神经化学信号的理解，并将突出特定的多巴胺释放模式，当这些模式被阻止时，可能会削弱与药物相关的线索如何促进药物寻找。动机通常在使用累进比率(PR)强化计划的操作性任务中进行评估。在公关增援计划期间，增强剂的净值随着获得增强剂的操作要求在随后的试验中增加而减少，直到操作响应停止为止，这是“转折点”，是一个人为获得增强剂所花费的激励努力的衡量标准。虽然NAcc中的多巴胺释放与动机操纵者的输出有关，但令人惊讶的是，人们对动机行为中多巴胺的短暂释放模式知之甚少。NAcc中的时相(亚秒)多巴胺释放先于目标定向动作的启动，这表明多巴胺的时相释放与动机行为有关。然而，在明确评估动机的行为范式中，多巴胺是如何被释放到与增强剂可获得性相关的线索上的，目前还不清楚。在这方面，这项建议通过利用伏安法来确定NAcc中阶段性、亚秒级的多巴胺释放在提示预测大鼠在具有天然增强剂(目标1)或滥用药物(目标2)的PR强化时间表的可操作性任务期间可用增强剂的作用来解决这一实验问题。吸毒成瘾的一个关键组成部分是增强购买毒品的动机，这涉及多巴胺的行为，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。这项建议研究了亚秒多巴胺释放在天然(食物)和药物(可卡因)增强剂的动机追求中的作用，这将增强我们对动机行为涉及的神经化学信号的理解，并将强调特定的多巴胺释放模式，当被阻止时，可能会降低追求药物的动机。

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.