Variation in the abilty of drug cues to reinstate drug seeking

描述（由申请人提供）：上瘾者很难抗拒与吸毒有关的线索。这些线索吸引了他们的注意力，把他们吸引到有毒品的地方，并激发了他们继续寻求毒品的行为——往往导致他们在表达了停止使用毒品的愿望之后再次吸毒。作为巴甫洛夫条件反射的结果，药物线索被认为获得了激励动机属性（“激励显著性”），即先前的中性刺激获得了条件刺激（CS）属性。然而，在使用大鼠的临床前研究中，我们发现个体在将奖励线索归因于激励显著性的程度上存在显著差异。奖励线索可能是一种非常有效的CS，在所有动物中都能唤起条件反应（CR），但只有在某些动物中才具有强烈的刺激作用。只有当奖励线索起到激励刺激的作用时，它们才会吸引、煽动、刺激和激励，从而导致潜在的适应不良行为。因此，我假设，倾向于将奖励线索归因于激励显著性的个体将特别难以抵制它们，并且特别容易复发。事实上，药物线索引发药物渴求和复发的能力存在相当大的差异。此外，这些线索增加吸毒欲望的程度与线索增加多巴胺（DA）传递的程度相关。在当前的应用中，我提出了一系列临床前研究，以调查复发行为的个体差异及其与DA传输的关系（使用快速扫描循环伏安法测量）。这一建议将解决以下问题：1)个体在将激励价值归因于奖励线索的倾向上的差异是否可以预测非偶然药物线索的恢复差异？2)阶段性DA释放的差异是否编码了线索诱导恢复的变异？这些研究有可能显著改变我们对成瘾和复发的个体脆弱性的看法，并指出更有针对性的干预措施。

DESCRIPTION (provided by applicant): Addicts have great difficulty resisting cues that have been associated with drug use. Such cues attract their attention, draw them to locations where drugs are located, and motivate continued drug-seeking behavior - often leading to relapse even in the face of an expressed desire to discontinue drug use. Drug cues are thought to acquire incentive motivational properties ("incentive salience") as a consequence of Pavlovian conditioning, whereby previously neutral stimuli acquire conditional stimulus (CS) properties. However, in preclinical studies using rats we have discovered that individuals vary markedly in the extent to which they attribute incentive salience to reward cues. A reward cue may act as a perfectly effective CS, evoking a conditional response (CR) in all animals, but function as a potent incentive stimulus only in some. Only if reward cues act as incentive stimuli do they come to attract, instigate, spur, and motivate, leading to potentially maladaptive behavior. I hypothesize, therefore, that individuals prone to attribute incentive salience to reward cues will have particular difficulty resisting them and will be especially vulnerable to relapse. Indeed, there is considerable variation in the ability of drug cues to instigate drug craving and relapse. Moreover, the degree that such cues increase the desire to take drug is correlated with how much the cue increases dopamine (DA) transmission. In the current application, I propose a series of preclinical studies to investigate individual variation in relapse behavior and its relationship with DA transmission (as measured using fast-scan cyclic voltammetry). This proposal will address the following questions: 1) Does individual variation in the tendency to attribute incentive value to reward cues predict variation in reinstatement to noncontingent drug cues? and 2) Do differences in phasic DA release encode variation in cue-induced reinstatement? These studies have the potential to significantly shift how we think about individual vulnerability to addiction and relapse, and point toward better-targeted interventions. PUBLIC HEALTH RELEVANCE: Addiction is a major public health problem in the United States, and the biggest threat to addicts is a high propensity to relapse. The goal of this project is to use a preclinical model to explore the psychological and neurobiological basis of individual variation in vulnerability to relapse, as this will help identify risk factors that will aid in the development of targeted interventions and treatments.