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

描述（由申请人提供）：从酒精滥用到成瘾的转变受到外部（环境）和内部（生物）线索对酒精寻求行为的控制的极大影响。在这种行为消失期间发生的新学习被认为比最初的关联更容易受到干扰，因此很容易被简单的酒精和/或先前与酒精相关的线索所破坏。由于它可以很容易地被触发，酒精和药物寻求行为的复发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%的依赖性患者在治疗后会复发。因此，必须更好地了解决定复发的因素，以减少康复者恢复有害的酒精和毒品相关行为的可能性。由于酒精仍然是最常用的精神活性药物，了解酒精配对线索如何触发康复后的寻酒行为对预防复发非常重要。该项目旨在了解小鼠酒精寻求行为消失和复发的神经生物学机制。使用一种新的行为程序，结合酒精条件性位置偏爱（CPP）和巴甫洛夫-指令性转移（PIT）程序，我们将首先使用激活的转录因子的表达来识别由复发诱导线索刺激的脑区，然后检查这些区域的神经元失活对线索诱导的复发行为的表达的影响。目的1建议使用免疫组织化学定位 技术，以评估磷酸化转录因子，pCREB和pElk-1的区域蛋白表达后立即暴露于一个线索，诱导复发的酒精寻求行为的小鼠。目标2将通过使用利多卡因的位点特异性显微注射来操纵这些区域的神经元活动，来检查不同脑区域对线索诱导的复发的表达的贡献，从而补充这些实验。通过结合分子，神经药理学和行为技术，这些拟议的实验是专门针对进一步了解线索诱导复发的酒精滥用治疗后的神经生物学机制。

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.