Individual Differences in Incentive Salience Attribution: Relevance to Addiction

描述(申请人提供)：虽然有些人能够随意使用药物而不会干扰他们的日常活动，但另一些人会上瘾，无法将他们的思想和行动从毒品和与药物相关的刺激中转移出来。这些个体差异背后的因素尚不清楚，但一个看似合理的解释是，成瘾倾向的个体差异与与奖励相关的线索控制行为的程度有关。与奖励相关的刺激获得行为控制的能力可以在实验室中使用巴甫洛夫条件反射程序进行研究。当一个离散的线索可靠地与收到奖励相匹配时，它不仅可以作为奖励的预测指标，还可以引发复杂的情绪和动机状态。因此，对于一些动物，即目标追踪者，与奖励相关的线索仅仅是一个预测者，引出了指向奖励传递位置的方法；而对于另一些动物，作为符号追踪者，线索获得了针对线索的动机价值、引出方法和完成性行为。符号跟踪行为被认为反映了激励显著对奖励相关线索的归因增强，因此可能与成瘾行为和复发的研究特别相关。因此，有效的假设是，体征追踪者可能代表着更容易上瘾的人；而目标追踪者可能代表那些对这种疾病有弹性的人。为了验证这一假设，我们将利用一种独特的遗传动物模型--根据一种寻求新奇的特征选择性繁殖的大鼠，但已知它们在一些与成瘾相关的特征上存在分歧。繁殖的高反应大鼠(BHR)主要是手势跟踪器，表现出对与食物和药物(可卡因)奖励相关的线索的处理；而繁殖的低反应大鼠(BHR)几乎完全是目标追踪器，接近奖励传递的位置。杂交中间反应者(BIR)的行为类似于商业大鼠，发展目标跟踪或手势跟踪行为的概率几乎相等。利用所有这三条线将在人群中提供一个连续体，使我们能够检查各种特征(例如，寻求新奇、跟踪手势)与成瘾倾向之间的关系。将获得以下药物滥用易感性指数：i)在长时间(5小时)的可卡因自我给药期间药物摄入量的增加；ii)在药物不再可用时的持续吸毒行为；iii)对灭绝的抵抗力；以及iv)在30天戒毒期后提示诱导的恢复(即复发)。从这些成瘾倾向的衡量标准中，将确定与目标跟踪的大鼠相比，标志跟踪的大鼠是否更容易过渡到成瘾。此外，选择性繁殖的大鼠品系的使用为未来的研究提供了巨大的潜力，以调查与成瘾行为相关的特征的遗传、分子和行为前因。公共卫生相关性：拟议的项目将检查与奖励相关的线索控制行为的程度上的个体差异是否与药物滥用脆弱性有关。利用选择性繁殖的大鼠品系，这些研究可能被证明在理解导致成瘾发展的心理、神经生物学和遗传机制方面非常有用。此外，拟议的动物模型可能会让我们确定是什么让一些人容易上瘾，以及是什么保护其他人不会发展成这种疾病。

DESCRIPTION (provided by applicant): While some individuals are able to casually use a drug without it interfering with their day-to-day activities, others become addicted, unable to shift their thoughts and actions away from drugs and drug-associated stimuli. The factors underlying these individual differences are not yet known, but one plausible explanation is that individual differences in addiction liability are related to the extent to which reward-related cues come to control behavior. The ability of reward-related stimuli to gain control over behavior can be studied in the laboratory using Pavlovian conditioning procedures. When a discrete cue is reliably paired with the receipt of a reward, it not only serves as a predictor of reward, but can also elicit complex emotional and motivational states. Thus, for some animals, goal-trackers, the reward-related cue serves merely as a predictor, eliciting approach directed toward the location of reward delivery; and for others, sign-trackers, the cue attains motivational value, eliciting approach and consummatory behavior directed towards the cue. Sign-tracking behavior is thought to reflect enhanced attribution of incentive salience to reward-related cues and may therefore be especially relevant to the study of addictive behavior and relapse. The working hypothesis then is that sign-trackers may represent individuals with increased vulnerability to addiction; whereas goal-trackers may represent those that are resilient to the disorder. To test this hypothesis, we will utilize a unique genetic animal model-rats selectively bred on the basis of a novelty-seeking trait but known to diverge on a number of traits relevant to addiction. Bred high-responder rats (bHR) are primarily sign-trackers, exhibiting approach to cues associated with both food and drug (cocaine) reward; and bred low-responder rats (bLR) are almost exclusively goal-trackers, approaching the location of reward delivery. Cross-bred intermediate responders (bIR) behave similarly to commercial rats, with almost equal probability of developing either goal-tracking or sign-tracking behavior. Utilizing all three of these lines will provide a continuum in the population, enabling us to examine the relationship between various traits (e.g. novelty-seeking, sign-tracking) and addiction liability. The following indices of substance abuse vulnerability will be obtained: I) escalation of drug intake during prolonged (5-hr) cocaine self-administration sessions; II) the persistence of drug-taking behavior when the drug is no longer available; III) resistance to extinction; and IV) cue-induced reinstatement (i.e. relapse) following a 30-day abstinence period. From these measures of addictive liability it will be determined whether rats that sign-track are more susceptible to the transition to addiction relative to rats that goal-track. Moreover, the use of the selectively bred rat lines provides enormous potential for future studies to investigate the genetic, molecular and behavioral antecedents to traits relevant to addictive behavior. PUBLIC HEALTH RELEVANCE: The proposed project will examine whether individual differences in the extent to which reward-related cues come to control behavior are related to substance abuse vulnerability. Utilizing selectively bred rat lines, these studies may prove to be very informative in understanding the psychological, neurobiological, and genetic mechanisms that contribute to the development of addiction. Moreover, the proposed animal model may allow us to determine what renders some individuals susceptible to addiction and what protects others from developing the disorder.