The Role of Activity-Regulated Cytoskeletal-Associated Protein in Amphetamine Pla

描述(申请人提供)：根据成瘾的激励敏感化理论，导致强迫性药物追逐的成瘾的关键变化是与药物相关的线索进行敏化动机反应的能力，这反过来又导致更强的药物追逐。在这种观点下，问题不是环境线索和药物之间形成异常和/或过于强烈的联系，而是药物相关刺激参与大脑动机系统的能力增强。背景条件刺激和药物非条件刺激之间的联系在杏仁基底外侧核形成。条件位置偏好(CPP)范式模拟了上下文线索和滥用药物的奖励效应之间的关联的形成，有证据表明，上下文和药物之间的关联的形成伴随着杏仁核基底外侧突触的增加(Rademacher等人)。2006)。活性调节细胞骨架相关蛋白(Arc)是由急性精神刺激药物(Tan等人，2000)和导致长期突触修改的行为经验(Kelly&Deadwyler，2003)诱导的。重要的是，树突棘中Arc蛋白的表达与突触形成的开始有关(Wang&Pickel，2004)。在这一应用中，将检验苯丙胺(AMPH)诱导CPP靶向树突结构的假设，如锥体神经元的脊椎和/或杏仁核基底外侧中间神经元的树突。如果数据支持这一假设，那么通过阻断Arc可以扰乱对与药物配对的上下文线索的记忆，这将减少对毒品的渴望和寻求行为，并降低复发的可能性。在具体目标1中，将使用双标记免疫组织化学和激光扫描共聚焦显微镜来确定Amph Place条件化是否改变杏仁核基底外侧锥体神经元和/或中间神经元中Arc的表达。在具体目标2中，将使用光学显微镜、免疫过氧化物酶/免疫金双标技术、电子显微镜和无偏向体视学来确定Amph Place条件反射是否改变了杏仁基底外侧锥体神经元和/或中间神经元树突结构中Arc的表达。在人类成瘾者中，暴露在以前与药物使用有关的环境线索中，强烈增加了复发的风险。开发有效的成瘾治疗方法需要更好地了解导致寻求毒品行为的神经底物。这项提议旨在研究在环境背景和药物之间反复配对后，杏仁基底外侧核的神经回路是如何改变的。

DESCRIPTION (provided by applicant): According to incentive-sensitization theory of addiction, the critical change in addiction leading to compulsive drug pursuit is in the ability of drug-associated cues to engage a sensitized motivational response that, in turn, leads to enhanced drug pursuit. In this view, the problem is not the formation of aberrant and/or excessively strong associations between environmental cues and drug, but rather enhanced ability of drug-associated stimuli to engage brain motivational systems. Associations between a contextual conditioned stimulus and the drug unconditioned stimulus are formed in the basolateral amygdala. The conditioned place preference (CPP) paradigm models the formation of the associations between contextual cues and the rewarding effects of drugs of abuse and there is evidence to suggest that formation of associations between context and drug is accompanied by increased synapses in the basolateral amygdala (Rademacher et al. 2006). Activity-regulated cytoskeletal associated protein (Arc) is induced by acute psychostimulant administration (Tan et al., 2000) and behavioral experience that leads to long-lasting synaptic modifications (Kelly & Deadwyler, 2003). Importantly, there is a correlation between Arc protein expression in dendritic spines and the onset of synaptogenesis (Wang & Pickel, 2004). In this application, the hypothesis that amphetamine- (AMPH) induced CPP targets Arc to dendritic structures such as the spines of pyramidal neurons and/or dendrites of interneurons of the basolateral amygdala will be tested. If the data support this hypothesis, then memories for contextual cues paired with drug could be disrupted by blocking Arc, which would diminish drug-craving and drug-seeking behavior and decrease the probability of relapse. In Specific Aim 1, dual-label immunohistochemistry and laser-scanning confocal microscopy will be used to determine whether AMPH place conditioning alters Arc expression in basolateral amygdala pyramidal neurons and/or interneurons. In Specific Aim 2, light microscopy, a dual label immunoperoxidase/immunogold technique, electron microscopy, and unbiased stereology will be used to determine whether AMPH place conditioning alters Arc expression in dendritic structures of pyramidal neurons and/or interneurons in the basolateral amygdala. In human addicts, exposure to environmental cues previously associated with drug use strongly increases the risk of relapse. Developing effective treatments for addiction requires a better understanding of the neural substrates responsible for drug-seeking behavior. This proposal is intended to study how the neural circuitry in the basolateral amygdala is altered after repeated pairings between environmental context and drug.