CBP Acetyltransferase Function in Addictive Behavior

CBP 乙酰转移酶在成瘾行为中的作用

• 批准号: 7290942
• 负责人: MARK R MAYFORD
• 金额: $ 18.05万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-25 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7290942
• 关键词: Abstinence; Acetyltransferase; Addictive Behavior; Address; Affect; Behavioral; Brain; CREB-binding protein; CREB1 gene; Chromatin Structure; Clinical; Clinical Trials; Cocaine; Complex; Condition; Cues; DNA; Development; Dominant-Negative Mutation; Drug Addiction; Epigenetic Process; Gene Expression; Genetic Transcription; Heart; Histone Deacetylase Inhibitor; Individual; Intake; Learning; Link; Measures; Mediating; Memory; Modeling; Modification; Molecular; Mutant Strains Mice; Neurons; Numbers; Operant Conditioning; Pharmaceutical Preparations; Phenotype; Process; Public Health; Range; Relapse; Research Personnel; Rewards; Specificity; Testing; Therapeutic; Therapeutic Intervention; Transcription Coactivator; Transcriptional Regulation; Wild Type Mouse; Withdrawal; Work; addiction; base; behavioral sensitization; drug of abuse; follow-up; histone acetyltransferase; human CREBBP protein; inhibitor/antagonist; long term memory; reinforcer; response; transcription factor

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.

描述（由申请人提供）：药物成瘾有很多组成部分，包括药物的直接奖励效应、药物摄入量的增加、强迫性药物寻求以及甚至在戒断多年后仍有复发的倾向，这可能是最难解决的组成部分从临床角度来看。从本质上讲，成瘾者大脑的变化代表了一种持久的神经元适应，这种适应必须具有潜在的细胞和分子成分。这使得一些研究人员提出，类似于介导记忆中正常学习的机制也与成瘾有关。多年来人们都知道，持久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非常持久的变化，并且与 CREB ​​和 fos 等转录因子的合作支持了这样的观点：成瘾和正常记忆可能具有共同的潜在分子机制。转录调控是一个复杂的过程，不仅需要向 DNA 募集转录因子，还需要对染色质结构进行特异性修饰。这些表观遗传修饰至关重要，我们最近使用突变小鼠证明，转录共激活因子 CBP 的组蛋白乙酰转移酶功能对于正常长期记忆的发育是必需的。此外，我们表明，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 是基于 CREB ​​的转录的主要共激活因子，这与各种成瘾模型有关，因此我们假设 CBP 组蛋白乙酰转移酶功能对于这些范例中的持久神经元调节也可能至关重要。因此，我们将研究可卡因精神运动激活效应的行为敏化（一种非联想过程），以及可卡因敏化的情境特异性（CBP 突变小鼠的联想过程）。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控制的理解，并确定潜在治疗干预的新靶点。