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

描述（由申请人提供）：根据成瘾的激励-敏化理论，成瘾导致强迫性药物追求的关键变化是药物相关线索参与敏化动机反应的能力，进而导致增强的药物追求。从这个角度来看，问题不在于环境线索和药物之间形成异常和/或过度强烈的联系，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关联在杏仁核基底外侧形成。条件位置偏好（CPP）范式模拟了情境线索和药物滥用奖励效应之间关联的形成，有证据表明，情境和药物之间关联的形成伴随着基底外侧杏仁核突触的增加（Rademacher et al. 2006）。活性调节的细胞骨架相关蛋白（Arc）是由急性精神兴奋剂（Tan etal ., 2000）和行为经验诱导的，从而导致持久的突触修饰（Kelly & Deadwyler, 2003）。重要的是，树突棘中Arc蛋白的表达与突触发生的发生之间存在相关性（Wang & Pickel, 2004）。在这个应用中，安非他明（AMPH）诱导CPP靶点Arc到树突结构，如锥体神经元的棘和/或杏仁核基底外侧中间神经元的树突的假设将被验证。如果数据支持这一假设，那么通过阻断Arc可以破坏与药物相关的情境线索的记忆，从而减少药物渴望和药物寻求行为，降低复发的可能性。在Specific Aim 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位置调节是否会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Specific Aim 2中，将使用光学显微镜、双标记免疫过氧化物酶/免疫金技术、电子显微镜和无偏立体学来确定AMPH位置条件反射是否会改变杏仁核基底外侧锥体神经元和/或中间神经元树突结构中的Arc表达。在人类成瘾者中，暴露于先前与吸毒有关的环境线索会大大增加复发的风险。开发有效的成瘾治疗方法需要更好地了解负责寻求药物行为的神经基质。本研究旨在研究环境背景和药物反复配对后基底外侧杏仁核神经回路的变化。

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.