CBP Acetyltransferase Function in Addictive Behavior

描述（由申请人提供）：药物成瘾有许多组成部分，包括药物的即时奖励作用、药物摄入量的增加、强迫性药物寻求和甚至在戒断多年后复发的倾向，这可能是从临床角度来看最难解决的组成部分。成瘾者大脑的变化代表了一种长期的神经适应，这种适应必须有一个潜在的细胞和分子组成部分。这使得一些研究人员提出，与介导正常记忆学习的机制类似的机制也参与了成瘾。多年来，人们已经知道，长期记忆的巩固需要新的基因表达。这是一种特别有吸引力的机制，可以介导神经元功能的长期变化，并且与CREB和fos等转录因子的合作支持了成瘾和正常记忆可能具有共同的潜在分子机制的观点。转录调控是一个复杂的过程，不仅需要将转录因子募集到DNA中，还需要对染色质结构进行特异性修饰。这些表观遗传修饰是至关重要的，我们最近已经证明，使用突变小鼠的组蛋白乙酰转移酶功能的转录辅激活因子CBP是必要的发展正常的长期记忆。此外，我们发现，这些行为缺陷可以克服使用组蛋白去乙酰化酶抑制剂目前在初步临床试验。由于CBP是一个主要的共激活CREB为基础的转录，这已经牵连在各种成瘾模型，我们假设CBP组蛋白乙酰转移酶功能可能是至关重要的，在这些范例以及持久的神经元调制。因此，我们将研究可卡因的精神激活作用的行为敏化，一个非关联的过程，以及可卡因敏化的上下文特异性，CBP突变小鼠的关联过程。如果出现缺陷，我们将测试组蛋白去乙酰化酶抑制剂挽救这些表型的能力。通过这种方式，我们希望扩大我们对成瘾机制的转录控制的理解，并确定潜在的治疗干预的新靶点。

DESCRIPTION (provided by applicant): Drug addiction has many components ranging from the immediate rewarding effects of the drug, escalation of drug intake, compulsive drug seeking and a tendency to relapse even many years after withdrawal, which can be the most difficult component to address from a clinical perspective. At its heart the changes in the addict's brain represent a long-lasting neuronal adaptation that must have an underlying cellular and molecular component. This has led some researchers to propose that mechanisms similar to those that mediate normal learning in memory are also involved in addiction. It has been known for many years that the consolidation of long-lasting memories requires new gene expression. This is a particularly attractive mechanism for mediating very long-lasting changes in neuronal function and work with transcription factors such as CREB and fos have supported the notion that addiction and normal memory may have common underlying molecular mechanisms. Transcriptional regulation is a complex process that requires not only the recruitment of transcription factors to the DNA but also specific modifications of chromatin structure. These epigenetic modifications are of critical importance and we have recently demonstrated using a mutant mouse that the histone acetyltransferase function of the transcriptional coactivator CBP is necessary for the development of normal long-term memory. Moreover, we showed that these behavioral deficits could be overcome using a histone deacetylase inhibitor currently in preliminary clinical trials. Since CBP is a major coactivator for CREB based transcription, which has been implicated in various addiction models, we postulate that CBP histone acetyltransferase function may be critical for long-lasting neuronal modulation in these paradigms as well. We will therefore examine behavioral sensitization of the psychomotor activating effects of cocaine, a nonassociative process, and the context-specificity of cocaine sensitization, an associative process in the CBP mutant mice. If deficits are obtained we will test the ability of histone deacetylase inhibitors to rescue these phenotypes. In this way we hope to expand our understanding of the transcriptional control of addictive mechanisms and identify new targets for potential therapeutic intervention.