Treatment of Opiate Dependence through Inhibition of Fatty Acid Amide Hydrolase

描述（由申请人提供）：这个职业发展奖提案（通过脂肪酸酰胺水解酶抑制剂治疗阿片类药物依赖）建立在候选人以前的培训基础上，通过抑制其降解酶增强内源性大麻素张力的行为效应领域，以及阿片类药物自我管理和依赖模型领域。该提案的目的是检查和跟踪候选人产生的数据，这些数据表明，长期抑制脂肪酸酰胺水解酶（FAAH），负责降解内源性大麻素anandamide的主要酶，减缓了海洛因自我给药模型中依赖的进展，同时也减缓了应激激素皮质酮血清水平的增加。为了有效地确定这些现象背后的机制和神经生物学，将需要训练来检查动物的奖励状态，在海洛因使用的进展过程中，使用颅内自我刺激。此外，学习有效表征海洛因滥用引起的神经系统变化所需的生物化学技术，以及FAAH抑制所逆转的生物化学技术，将使我们更好地了解对预防海洛因依赖进展至关重要的大脑区域和适应性。将采用的生化措施将包括：基因表达，蛋白质定量，酶活性和内源性大麻素定量。在内源性大麻素活性生物化学测量领域的专家Benjamin Cravatt博士的指导下，沿着通过乔治库布博士的支持提供的药物滥用相关行为模型的专业知识，候选人将能够整合证据的趋同线，以证明奖励和压力在内源性大麻素系统对抗阿片类药物成瘾的效用中发挥的作用。斯克里普斯研究所的环境也将被用来提供培训，这将提高候选人的职业生涯作为一个独立的调查员，包括在有效的实验室管理和适当的研究行为的专门课程准备。该项目将重点关注FAAH抑制在阿片类药物依赖治疗中具有或可能具有治疗优势的机制。奖励阈值的变化，这是建立增加海洛因的使用，假设在FAAH抑制剂治疗的存在下被正常化。此外，将在存在和不存在FAAH抑制剂治疗的情况下检查停药期间与负面情感样状态相关的生化变化，例如CRF和糖皮质激素受体表达的变化。这些生化变化将被海洛因戒断诱导的焦虑和抑郁样行为的测量所证实。最后，一代的遗传靶向FAAH缺陷的大鼠将允许检查的变化，由于长期的海洛因戒断，长期FAAH失活的复发易感性海洛因在药物，线索和应激源的存在下，与压力相关的基因。结合起来，该项目将进一步科学地了解海洛因成瘾，药物成瘾作为一种重复压力的形式，内源性大麻素通过减少与药物有关的压力源和快感缺失来打破药物滥用循环的作用。

DESCRIPTION (provided by applicant): This career development award proposal (Treatment of Opiate Dependence through Inhibitors of Fatty Acid Amide Hydrolase) builds upon previous training of the candidate, in the area of the behavioral effects of enhancing endocannabinoid tone via inhibition of their degradative enzymes, and in the area of models of opioid self-administration and dependence. The aim of this proposal is to examine and follow up on data produced by the candidate that suggests that chronic inhibition of fatty acid amide hydrolase (FAAH), the primary enzyme responsible for degrading the endocannabinoid anandamide, blunts the progression of dependence in a heroin self-administration model while also blunting increases in the serum levels of the stress hormone corticosterone. To effectively determine the mechanisms and neurobiology underlying these phenomena will require training to examine the reward state of the animals, during the progression of heroin use, using intracranial self-stimulation. In addition, learning biochemical techniques required toward effectively characterizing the neurological changes occurring due to heroin abuse, and that which is reversed by FAAH inhibition, will allow a greater understanding of the brain regions and adaptations critical to preventing the progression of heroin dependence. Biochemical measures that will be employed will include: gene expression, protein quantification, enzyme activity, and endocannabinoid quantification. Under the tutelage of Dr. Benjamin Cravatt, an expert in the area of biochemical measure of endocannabinoid activity, along with the expertise in drug-abuse related behavioral models provided through the support of Dr. George Koob, the candidate will be able to integrate converging lines of evidence to demonstrate the roles that reward and stress play in the utility of the endocannabinoid system against opioid addiction. The Scripps Research Institute environment will also be utilized to provide training that will enhance the readiness of the candidate for a career as an independent investigator, including specialized courses in effective lab management and proper research conduct. The project will focus on the mechanisms by which FAAH inhibition are, or could potentially be, therapeutically advantageous in the treatment of opioid dependence. Changes in reward thresholds, which are established to increase with heroin use, are hypothesized to be normalized in the presence of FAAH inhibitor treatment. Furthermore, biochemical changes associated with negative affective-like states during drug withdrawal, exemplified by changes in CRF and glucocorticoid receptor expression, will be examined in the presence and absence of treatment with FAAH inhibitors. These biochemical changes will then be corroborated by heroin withdrawal-induced measures of anxiety- and depressive-like behaviors. Finally, the generation of a genetically-targeted FAAH-deficient rat will allow the examination of changes in stress-related genes due to protracted heroin withdrawal, and long-term FAAH inactivation on the relapse susceptibility to heroin in the presence of drug, cues, and stressors. Combined, the project will further the science on the understanding on heroin addiction, drug addiction as a form of repeated stress, the role of endocannabinoids to break the cycle of drug abuse through the reduction of drug-associated stressors and anhedonia.