Neural Substrates of Stimulus-Induced Drug Seeking

描述(申请人提供)：对以前与吸毒有关的刺激作出反应而寻求毒品，对吸毒成瘾个人的再犯罪有很大贡献，因为呈现与毒品有关的刺激可引起对毒品的强烈渴望，从而导致复发。与药物相关的线索也起到条件反射的强化作用，以维持或建立复杂的药物寻找行为。在成瘾的动物模型中，与毒品相关的刺激既能诱导并维持寻求毒品的行为。相当多的研究已经检验了这种药物相关的条件性增强子在维持药物寻找行为中所起作用的神经回路。明显较少的研究考察了与药物相关的辨别性刺激诱导药物寻找行为的能力背后的神经基础。此外，发生可塑性和随后的神经活动产生药物相关线索对药物寻找行为的这些不同影响的神经回路是否重叠或不同还没有很好的定义。然而，有证据表明，在涉及的电路中可能存在差异。最后，分子底物的激活，如活性调节细胞骨架相关蛋白(ARC)、Zif268和c-fos，被认为是学习和记忆的突触可塑性基础，在研究药物相关线索在药物寻找行为的启动和维持中的作用的研究中，仅在非常有限的程度上进行了检查。因此，这一提议将检验这样一个假设，即引发寻药行为的可卡因相关歧视刺激激活了神经元群体中突触可塑性的分子级联，这些突触可塑性与维持寻药行为的可卡因相关条件性增强子诱导这些分子的机制截然不同，但又有一些重叠。这一假说将通过荧光原位杂交(CATFISH)时间活动的细胞室分析来验证，以评估暴露于两种药物相关刺激下的动物的这两种类型刺激激活的大脑区域，以及这些基因是否在给定大脑区域的同一神经元群中被激活。这些信息将使人们更好地了解刺激诱导的药物寻求行为背后的系统水平和分子基础，这应该转化为改进对刺激诱导的药物成瘾复发的治疗管理。对以前与吸毒有关的刺激作出反应而寻求毒品，对吸毒成瘾者的再犯有很大贡献，因为呈现与毒品有关的刺激可引起强烈的对毒品的渴望，从而导致复发。这个项目将研究药物相关刺激参与的神经电路，这些刺激诱导和维持药物寻找行为，以及分子底物的激活，这些分子底物被认为是学习和记忆的突触可塑性基础。将获得的数据将为刺激诱导的药物寻求行为背后的系统水平和分子底物提供关键的、新颖的见解，这将转化为改进对刺激诱导的药物成瘾复发的治疗管理。

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.