Variation in the abilty of drug cues to reinstate drug seeking

描述（由申请人提供）：成瘾者很难抵抗与药物使用相关的线索。这些线索吸引了他们的注意力，将他们吸引到毒品所在的地方，并促使他们继续寻求毒品的行为-即使他们表达了停止吸毒的愿望，也往往导致复吸。药物线索被认为是获得激励动机属性（“激励显着性”）作为巴甫洛夫条件反射的结果，其中先前中性刺激获得条件刺激（CS）属性。然而，在使用大鼠的临床前研究中，我们发现个体在将激励显着性归因于奖励线索的程度上存在显着差异。奖励线索可以作为一个完全有效的CS，唤起所有动物的条件反应（CR），但功能作为一个强有力的激励刺激只有在一些。只有当奖励线索作为激励刺激时，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，倾向于将激励显著性归因于奖励线索的个体将特别难以抵制它们，并且特别容易复发。事实上，药物线索诱发药物渴望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）传输的程度相关。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）。这个建议将解决以下问题：1）个体差异的倾向，属性奖励价值的奖励线索预测的变化，恢复到非偶然的药物线索？和2）相位DA释放的差异编码线索诱导的恢复的变化？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，并指向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.