Neural Substrates of Stimulus-Induced Drug Seeking

描述（由申请人提供）：对先前与吸毒有关的刺激作出的药物寻求对吸毒成瘾个体的再犯有显著影响，因为药物相关刺激的出现会引起对药物的强烈渴望，从而导致复发。药物相关线索也作为条件强化物维持或建立复杂的药物寻求行为。在成瘾的动物模型中，与药物相关的刺激可以引发并维持药物寻求行为。相当多的研究已经检查了这些药物相关的条件强化物在维持药物寻求行为中的作用的神经回路。对于药物相关的区别性刺激诱发药物寻求行为的神经基质的研究较少。此外，可塑性发生的神经回路和随后的神经活动对药物相关线索对药物寻找行为的不同影响是重叠的还是不同的，目前还没有很好的定义。然而，有证据表明，在相关的电路中可能存在差异。最后，分子底物的激活，如活性调节的细胞骨架相关蛋白（arc）、zif268和c-fos，被认为是突触可塑性的基础，是学习和记忆的基础，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时，只在非常有限的程度上进行了研究。因此，这一提议将验证这样一个假设，即引起药物寻找行为的可卡因相关的判别刺激激活了神经元群体突触可塑性基础上的分子级联，这与那些维持药物寻找行为的可卡因相关条件强化物诱导这些分子的神经元群体不同，但在某种程度上有重叠。这一假设将通过荧光原位杂交（catFISH）的时间活动细胞室分析来检验，以评估暴露于两种药物相关刺激的动物被这两种类型的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相同神经元群中被激活。这些信息将有助于更好地理解刺激诱导的药物寻求行为背后的系统水平和分子底物，这应该转化为改善刺激诱导的药物成瘾复发的治疗管理。对先前与吸毒有关的刺激作出的药物寻求对吸毒成瘾个体的再犯有显著影响，因为药物相关刺激的出现会引起对药物的强烈渴望，从而导致复发。该项目将研究由药物相关刺激引起并维持药物寻找行为的神经回路，以及被认为是学习和记忆基础突触可塑性基础的分子底物的激活。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基础提供关键的、新颖的见解，这应该转化为改善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.