CBP Acetyltransferase Function in Addictive Behavior

描述(由申请人提供)：吸毒成瘾有许多因素，从药物的直接回报效应、药物摄入量的增加、强迫寻求药物以及即使在戒断多年后也有复发的趋势，从临床角度来看，这可能是最难解决的因素。从本质上讲，上瘾者大脑的变化代表了一种长期的神经元适应，必须有潜在的细胞和分子成分。这导致一些研究人员提出，与调节记忆中正常学习的机制类似的机制也与成瘾有关。多年来，人们已经知道，长期记忆的巩固需要新的基因表达。这是一种特别吸引人的机制，可以调节神经元功能的非常持久的变化，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招募到DNA中，还需要对染色质结构进行特定的修饰。这些表观遗传修饰是至关重要的，我们最近用一只突变的小鼠证明了转录辅活化子CBP的组蛋白乙酰转移酶功能对于正常的长期记忆的发展是必要的。此外，我们还表明，使用目前处于初步临床试验中的组蛋白脱乙酰酶抑制剂可以克服这些行为缺陷。由于CBP是CREB转录的主要辅助激活因子，并与多种成瘾模型有关，我们推测CBP组蛋白乙酰转移酶的功能可能对这些范例中持久的神经元调节也是至关重要的。因此，我们将研究可卡因的精神运动激活效应的行为敏感化，这是一个非联想过程，以及可卡因敏化的上下文特异性，可卡因敏化是CBP突变小鼠的一个关联过程。如果获得缺陷，我们将测试组蛋白脱乙酰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转录调控的理解，并为潜在的治疗干预确定新的靶点。

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.