GENETIC ANALYSIS OF DRUG ADDICTION

随着时间的推移和反复服用，许多药物的滥用会导致身体依赖，当药物从系统中移除时表现为戒断综合症。药物作用是如何导致大脑中负责成瘾过程的持久变化的，目前尚不清楚。通过cAMP的信号传导已被证明在多种药物滥用的反应中是至关重要的。CREB （cAMP反应元件结合）蛋白已被确定为介导cAMP和Ca2+水平升高的转录反应的重要因子。利用基因靶向技术，已经产生了携带CREB基因突变的小鼠。这些小鼠表现出慢性吗啡戒断反应显著减少，这表明CREB参与了身体阿片类药物依赖。本研究计划的总体目标是评估CREB在药物诱导小鼠生化和行为改变中的作用。在Specific Aim 1中，我们将分析野生型和CREB缺陷小鼠cAMP/PKA/CREB通路的上游组分，以表征CREB蛋白缺失后细胞信号传导过程中的其他生化变化，这些变化可能与滥用药物的行为行为有关。在CREB突变小鼠中，耐受性或奖励特性的异常发展可能有助于减少慢性吗啡后纳洛酮沉淀戒断。在特异性目标2中，我们将评估CREB在使用CREB突变小鼠对吗啡的耐受性和条件性位置偏好的发展中的作用。CREB/ATF转录因子家族的第二个成员，即CREM，能够替代CREB的许多作用。在具体目标3中，我们将描述CREM在慢性吗啡耐受、依赖和戒断发展中的作用。在Specific Aim 4中，我们将通过检查CREB和CREM突变小鼠可卡因后行为致敏的诱导和发展，来确定CREB或CREM是否在其他形式的药物成瘾中具有更普遍的作用。在这里描述的研究计划中使用上述小鼠模型代表了明确的一步，以阐明与药物成瘾有关的生化和行为变化的分子基础。对这些神经生物学机制的全面理解将为未来更合理的药物成瘾治疗开辟新的视角。

Over time and with repeated administration many drugs of abuse will cause physical dependence that is expressed by a withdrawal syndrome when the drug is removed from the system. How drug effects lead to long lasting changes in the brain responsible for the addiction process is not well understood. Signaling via cAMP has been shown to be critical in the responses of a variety of drugs of abuse. The CREB (cAMP response element binding) protein has been identified as an important factor mediating a transcriptional response to elevated levels of cAMP and Ca2+. Using the techniques of gene targeting, mice have been generated which carry a mutation in the CREB gene. These mice exhibit a dramatically reduced withdrawal response following chronic morphine providing evidence that CREB is involved in physical opioid dependence. The overall goal of this research program is to evaluate the role of CREB in drug induced biochemical and behavioral changes in mice. In Specific Aim 1 we will analyze upstream components of the cAMP/PKA/CREB pathway in wild type and CREB deficient mice to characterize additional biochemical changes in cell signaling processes after deletion of the CREB protein that may be associated with behavioral actions of drugs of abuse. Abnormalities in the development of tolerance or rewarding properties may contribute to the reduction of naloxone precipitated withdrawal after chronic morphine in CREB mutant mice. In Specific Aim 2 we will evaluate the role of CREB in the development of tolerance and conditioned place preference to morphine using CREB mutant mice. A second member of the CREB/ATF family of transcription factors, namely CREM, is capable of substituting for many of the effects of CREB. In Specific Aim 3 we will characterize the role of CREM in the development of tolerance, dependence and withdrawal following chronic morphine. In Specific Aim 4, we will determine whether CREB or CREM has a more universal role in other forms of drug addiction by examining the induction and development of behavioral sensitization following cocaine in CREB and CREM mutant mice. The use of the above mouse models in the research program described here represent a definitive step to clarifying the molecular basis for the biochemical and behavioral changes involved in drug addiction. The complete understanding of these neurobiological mechanisms would open new perspectives for the future development of a more rational therapy for drug addiction.