Neural Substrates of Stimulus-Induced Drug Seeking

描述（由申请人提供）：对先前与药物使用相关的刺激做出反应的药物寻求在很大程度上导致药物成瘾个体的累犯，因为药物相关刺激的呈现可以引发对药物的强烈渴望，这有助于复发。药物相关的线索也作为条件反射器来维持或建立复杂的药物寻求行为。在成瘾的动物模型中，药物相关的刺激可以引起并维持药物寻求行为。相当多的研究已经检查了这种药物相关的条件反射在维持药物寻求行为中的作用的神经回路。显著较少的研究已经检查了与药物相关的辨别性刺激引起药物寻求行为的能力的神经基质。此外，发生可塑性的神经回路和随后的神经活动是否会产生药物相关线索对药物寻求行为的不同影响，这些影响是重叠的还是不同的，还没有很好的定义。然而，有证据表明，所涉及的电路可能存在差异。最后，分子底物的激活，如活性调节的细胞骨架相关蛋白（ARC），zif 268和c-fos，被认为是学习和记忆的基础突触可塑性的基础，在研究药物相关线索在药物寻求行为的启动和维持中的作用的研究中，只在非常有限的程度上进行了检查。因此，这项建议将测试的假设，可卡因相关的歧视性刺激，引发药物寻求行为激活的分子级联神经元群体的突触可塑性的基础是不同的，但有些重叠，在这些可卡因相关的条件反射，维持药物寻求行为诱导这些分子。将使用荧光原位杂交（catFISH）时间活动的细胞区室分析来检查这一假设，以评估暴露于两种药物相关刺激的动物中这两种类型刺激激活的脑区，以及这些基因是否在给定脑区的相同神经元群体中被激活。这些信息将允许更好地了解系统水平和分子底物的刺激诱导的药物寻求行为，这应该转化为改善治疗管理的刺激诱导复发的药物成瘾。对先前与吸毒有关的刺激作出反应而寻求毒品，在很大程度上导致吸毒成瘾者的累犯，因为与毒品有关的刺激的出现可引起对毒品的强烈渴望，从而导致复吸。该项目将研究与药物相关的刺激所涉及的神经回路，这些刺激引发并维持药物寻求行为，以及被认为是学习和记忆的基础突触可塑性的分子底物的激活。所获得的数据将提供关键的，新的洞察系统水平和分子底物刺激诱导的药物寻求行为，这应该转化为改善治疗管理刺激诱导的药物成瘾复发。

DESCRIPTION (provided by applicant): Drug-seeking in response to stimuli previously associated with drug use contributes significantly to recidivism in drug-addicted individuals, as presentation of drug-associated stimuli can elicit intense craving for drug, which contributes to relapse. Drug-associated cues also act as conditioned reinforcers to maintain or establish complex drug-seeking behaviors. In animal models of addiction, drug-associated stimuli can both elicit and maintain drug-seeking behavior. Considerable research has examined neural circuits underlying the role of such drug-associated conditioned reinforcers in the maintenance of drug-seeking behavior. Significantly less research has examined neural substrates underlying the ability of drug-associated discriminative stimuli to elicit drug-seeking behavior. Furthermore, whether the neural circuits in which plasticity takes place and subsequent neural activity produces these differing effects of drug-associated cues on drug-seeking behavior overlap or are distinct is not well defined. Evidence suggests, however, that there are likely to be differences in the circuits involved. Finally, activation of molecular substrates, such as activity regulated cytoskeletal- associated protein (arc), zif268, and c-fos, thought to underlie synaptic plasticity fundamental for learning and memory, has only been examined to a very limited extent in studies investigating the role of drug-associated cues in the initiation and maintenance of drug-seeking behavior. This proposal therefore will test the hypothesis that cocaine-associated discriminative stimuli that elicit drug-seeking behavior activate molecular cascades underlying synaptic plasticity in neuronal populations that are distinct from, yet somewhat overlapping with, those in which cocaine-associated conditioned reinforcers that maintain drug-seeking behavior induce these molecules. This hypothesis will be examined using cellular compartment analysis of temporal activity with fluorescent in situ hybridization (catFISH) to assess the brain regions activated by these two types of stimuli in animals exposed to both drug-associated stimuli and whether these genes are activated in the same neuronal populations in a given brain region. Such information will allow greater understanding of systems-level and molecular substrates underlying stimulus-induced drug-seeking behavior, which should translate into improved therapeutic management of stimulus-induced relapse in drug addiction. Drug seeking in response to stimuli previously associated with drug use contributes significantly to recidivism in drug-addicted individuals, as presentation of drug-associated stimuli can elicit intense craving for drug, which contributes to relapse. This project will examine the neural circuits engaged by drug-associated stimuli that elicit and maintain drug seeking behavior and the activation of molecular substrates thought to underlie synaptic plasticity fundamental for learning and memory. The data to be obtained will provide critical, novel insight into the systems-level and molecular substrates underlying stimulus-induced drug-seeking behavior, which should translate into improved therapeutic management of stimulus-induced relapse in drug addiction.