The neurobiology of cue-induced relapse to ethanol-seeking behavior in mice

描述(由申请人提供)：从酗酒到上瘾的转变很大程度上受到外部(环境)和内部(生物)线索对酒精寻求行为施加的控制的影响。与最初的联想相比，在这种行为消失期间发生的新学习被认为更容易受到干扰，因此很容易被简单的酒精呈现和/或之前与酒精相关的提示所干扰。由于它很容易被触发，再次酗酒和吸毒行为已被证明是人类成瘾者康复治疗中最困难的方面之一。事实上，据报道，50-90%的依赖患者在接受治疗后会复发。因此，必须更好地了解导致复发的因素，以减少康复个人重新回到有害的酒精和与毒品有关的行为的可能性。由于酒精仍然是最常用的精神活性药物，了解与酒精配对的线索是如何在康复后触发酒精寻求行为的，对于防止复发非常重要。该项目专门旨在了解小鼠酗酒行为消亡和复发的神经生物学机制。利用一种结合了酒精条件位置偏爱(CPP)和巴甫洛夫-仪器转移(PIT)程序的新的行为程序，我们将首先利用激活的转录因子的表达来识别复发诱导线索刺激的大脑区域，然后考察这些区域的神经元失活对线索诱导的复发行为表达的影响。目标1建议使用免疫组织化学标记法 评估磷酸化转录因子pCREB和pElk-1在暴露于诱导小鼠再次饮酒行为的线索后立即的区域蛋白表达的技术。目的2将通过使用特定部位的利多卡因微量注射来操纵不同大脑区域的神经元活动，来检验不同大脑区域对线索诱导的复发表达的贡献，以补充这些实验。通过结合分子、神经药理学和行为技术，这些拟议的实验专门旨在加深我们对线索诱导的酒精滥用治疗后复发的神经生物学机制的理解。

DESCRIPTION (provided by applicant): The transition from alcohol abuse to addiction is greatly influenced by the control with which both external (environmental) and internal (biological) cues exert over alcohol-seeking behavior. The new learning that occurs during the extinction of this behavior is thought to be more vulnerable to disturbance than the initial association and can therefore be easily disrupted by simple presentation of alcohol and/or the previously alcohol-associated cues. Because of the ease with which it can be triggered, relapse to alcohol and drug-seeking behavior has proven to be one of the most difficult aspects of rehabilitation therapy in human addicts. In fact, it has been reported that 50-90% of dependent patients will relapse following treatment. As such, it is imperative to better understand the factors that dictate the drive to relapse in order to reduce the likelihood that rehabilitated individuals return to harmful alcohol and drug-related behaviors. As alcohol continues to be the most commonly used psychoactive drug, understanding how alcohol-paired cues trigger alcohol-seeking behavior following rehabilitation is of great importance to the prevention of relapse. This project is specifically aimed at understanding the neurobiological mechanisms underlying the extinction of, and relapse to, alcohol-seeking behavior in mice. Using a novel behavioral procedure that combines alcohol-conditioned place preference (CPP) and Pavlovian-lnstrumental Transfer (PIT) procedures, we will first use the expression of activated transcription factors to identify the brain regions stimulated by a relapse-inducing cue and then examine the effects of neuronal inactivation of these regions on the expression of cue-induced relapse behavior. Aim 1 proposes to use immunohistochemical mapping techniques to assess the regional protein expression of the phosphorylated transcription factors, pCREB and pElk-1 immediately following exposure to a cue that induces relapse to alcohol-seeking behavior in mice. Aim 2 will compliment these experiments by examining the contributions of different brain regions to the expression of cue-induced relapse by manipulating the neuronal activity of these regions using site-specific microinjections of lidocaine. By combining molecular, neuropharmacological, and behavioral techniques, these proposed experiments are specifically aimed at furthering our understanding the neurobiological mechanisms underlying cue-induced relapse to alcohol abuse following treatment.