GENETIC ANALYSIS OF DRUG ADDICTION

随着时间的推移和重复给药，许多滥用药物将导致身体依赖，当药物从系统中移除时，表现为戒断综合征。 药物作用如何导致负责成瘾过程的大脑发生长期持续的变化，目前还不清楚。 通过cAMP的信号传导已被证明在各种滥用药物的反应中至关重要。 CREB（cAMP应答元件结合）蛋白已被鉴定为介导对升高水平的cAMP和Ca 2+的转录应答的重要因子。使用基因靶向技术，已经产生了在CREB基因中携带突变的小鼠。 这些小鼠在慢性吗啡后表现出显著降低的戒断反应，提供了CREB参与身体阿片依赖的证据。 本研究计划的总体目标是评估CREB在药物诱导的小鼠生化和行为变化中的作用。 在具体目标1中，我们将分析野生型和CREB缺陷小鼠中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可能与滥用药物的行为作用相关的其他生化变化。 在CREB突变小鼠中，耐受性或奖赏特性的发展异常可能有助于减少慢性吗啡后纳洛酮催促戒断。 在具体目标2中，我们将评估CREB的作用，在发展中的耐受性和条件性位置偏爱吗啡使用CREB突变小鼠。CREB/ATF转录因子家族的第二个成员，即CREM，能够取代CREB的许多作用。 在具体目标3中，我们将描述CREM在慢性吗啡耐受性、依赖性和戒断发展中的作用。 在具体目标4中，我们将通过检查CREB和CREM突变小鼠可卡因后行为敏化的诱导和发展，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澄清药物成瘾所涉及的生物化学和行为变化的分子基础的决定性步骤。 对这些神经生物学机制的全面了解将为未来开发更合理的药物成瘾治疗方法开辟新的前景。

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.