A Translational Model of Mood-Based Drug Abuse

描述（由申请人提供）：急迫性，或基于情绪的皮疹行为，是人类临床文献中定义的冲动的四个方面之一（Whiteside & Lynam, 2001; Cyders, Smith, Spillane, Fischer, Annus, & Peterson, 2007）。紧急的动物模型可以让我们进一步了解特定大脑系统在基于情绪的皮疹行为中的作用。通过操纵奖励预期，可以在实验室大鼠中测量行为结果（如强化遗漏效应或ROE） （Gipson, Zentall, & Bardo, in preparation）。吉普森等人试图在大鼠中使用操作性任务开发一种操作性紧急性动物模拟物。动物接受了最初的巴甫洛夫成分，其中一个条件刺激（关键光）与一个蔗糖颗粒的传递相匹配。随后，动物能够重复完成固定比例(FR)-10的强化计划，以获得一个蔗糖颗粒。在巴甫洛夫成分（遗漏试验）中，很少有蔗糖颗粒被递送。对两种试验类型的反应率进行了测量-在遗漏试验期间反应率增加（ROE效应）。这个程序可以量化紧急程度的个体差异。第一个提议的研究旨在检查遗漏预期的非药物奖励（蔗糖粒）对大鼠d-安非他明自我给药的影响。第二组研究旨在检验ROE的跨物种普遍性，通过使用模拟人类表现任务来检验紧迫性的个体差异，并确定这些个体差异是否反映了UPPS人格量表上的紧迫性得分。使用上述非人类动物程序的一种变体，将测试个体在意外忽略奖励后的反应率。金钱奖励将在两项人体研究中作为初始部分的非偶然预期奖励。受试者将被允许在终端组件的FR-100时间表上点击电脑鼠标，并将获得金钱（研究2a）或积分，这些积分可以兑换d-安非他明胶囊（研究2b）。为了更好地了解如何减少人类因情绪而产生皮疹的风险，量化紧急程度的个体差异是很重要的。虽然关于人类急迫性的神经系统的信息很少，但一个有效的动物鲁莽行为模型将为这些系统的更好研究提供基础。如果能更好地理解导致急症的神经行为原因，就能以更有效的方式降低风险。如果能开发出专门针对与急症有关的大脑区域的药物，那么易患急症的人的冲动性可能会降低。

DESCRIPTION (provided by applicant): Urgency, or mood-based rash action, is one of four facets of impulsivity defined in human clinical literature (Whiteside & Lynam, 2001; Cyders, Smith, Spillane, Fischer, Annus, & Peterson, 2007). An animal model of urgency may allow further understanding of the role of specific brain systems in mood-based rash action. By manipulating reward expectancy, behavioral outcomes (such as a reinforcement omission effect, or ROE) can be measured in laboratory rats (Gipson, Zentall, & Bardo, in preparation). Gipson et al. sought to develop an operant animal analogue of urgency using an operant task in rats. Animals received an initial Pavlovian component in which a conditioned stimulus (a key light) was paired with the delivery of one sucrose pellet. A terminal, operant component followed in which animals were able to repeatedly complete a fixed-ratio (FR)-10 schedule of reinforcement for one sucrose pellet. Infrequently, no sucrose pellet was delivered in the Pavlovian component (omission trials). Response rates were measured on both trial types - rates were increased during omission trials (an ROE effect). This procedure allowed individual differences in level of urgency to be quantified. The first proposed study is designed to examine the effects of omission of expected non-drug reward (sucrose pellets) on d-amphetamine self-administration in rats. The second proposed set of studies is designed to examine the cross-species generality of the ROE by examining individual differences in urgency using an analog performance task in humans, and to determine if these individual differences reflect urgency scores on the UPPS personality scale. Using a variation of the nonhuman animal procedure described above, individuals will be tested for response rates following unexpected omission of reward. Monetary reward will be used in both human studies as the non-contingent expected reward in the initial component. Subjects will be allowed to click a computer mouse on a FR-100 schedule in a terminal component, and will receive money (study 2a) or points that can be exchanged for capsules of d-amphetamine (study 2b). To better understand how to reduce risk for mood-based rash action in humans, it is important to quantify individual differences in urgency. While there is little information on the neural systems involved in human urgency, a valid animal model of rash action would provide a foundation upon which these systems can be better studied. If the neurobehavioral causes of urgency are better understood, risk can be reduced in a more effective way, and impulsivity in predisposed individuals may be reduced if drugs can be developed to specifically target these brain areas implicated in urgency. PUBLIC HEALTH RELEVANCE: Impulsivity is known to be a risk factor for various negative health-related behaviors, including drug abuse. This project will assess a behavioral model of impulsivity in both rat and human subjects to determine its usefulness in relation to personality questionnaires that are typically used to assess impulsivity in humans. This work will advance our basic knowledge about the neural mechanisms of impulsive behavior and drug abuse.