Variation in the abilty of drug cues to reinstate drug seeking

描述(由申请人提供)：吸毒者很难抵抗与药物使用有关的线索。这样的线索会吸引他们的注意力，把他们吸引到毒品所在的地方，并激发持续的毒品寻找行为--即使面对明确的戒毒愿望，往往也会导致复发。作为巴甫洛夫条件作用的结果，药物线索被认为获得了激励性动机特性(“激励性显著”)，即先前的中性刺激获得条件刺激(CS)特性。然而，在用大鼠进行的临床前研究中，我们发现，在将激励突显归因于奖励线索的程度上，个体存在显著差异。奖励线索可以作为一种完全有效的CS，在所有动物中引发条件反应(CR)，但只在某些动物中起到强有力的激励刺激的作用。只有当奖励暗示作为激励刺激时，它们才会吸引、煽动、鞭策和激励，从而导致潜在的不适应行为。因此，我假设，倾向于将激励突显归因于奖励暗示的人，将特别难以抵抗它们，特别容易复发。事实上，在药物线索激发药物渴望和复发的能力方面存在着相当大的差异。此外，这种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。在目前的应用中，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传递的关系(通过快速扫描循环伏安法测量)。这项建议将解决以下问题：1)将激励价值归因于奖励线索的倾向的个体差异是否预测了恢复非偶然药物线索的差异？2)在线索诱导的恢复过程中，DA时相释放的差异是否编码了变异？这些研究有可能显著改变我们对个体成瘾和复发易感性的看法，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.