Treatment of Opiate Dependence through Inhibition of Fatty Acid Amide Hydrolase

描述(由申请人提供)：这份职业发展奖提案(通过脂肪酸酰胺水解酶抑制剂治疗阿片依赖)建立在候选人之前的培训基础上，培训领域是通过抑制内源性大麻素降解酶来增强内源性大麻素的行为影响，以及阿片类药物自我给药和依赖模型领域。这项提案的目的是检查和跟踪候选人提供的数据，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脱氢酶的主要酶--可以减缓海洛因自我给药模型中的依赖进展，同时也减缓应激激素皮质酮水平的上升。为了有效地确定这些现象背后的机制和神经生物学，需要进行培训，以检查动物在海洛因使用过程中的奖励状态，使用颅内自我刺激。此外，学习有效描述海洛因滥用引起的神经变化所需的生化技术，以及通过抑制FAAH逆转的变化，将使人们更好地了解大脑中对防止海洛因依赖恶化至关重要的区域和适应。将采用的生化措施包括：基因表达、蛋白质定量、酶活性和内源性大麻素定量。在生物化学测量内源性大麻素活性领域的专家本杰明·克拉瓦特博士的指导下，再加上乔治·库布博士提供的与药物滥用相关的行为模型方面的专业知识，候选人将能够整合各种趋同的证据，以证明奖励和压力在内源性大麻素系统对抗阿片成瘾中的作用。还将利用斯克里普斯研究所的环境提供培训，加强候选人作为独立调查员的职业准备，包括关于有效实验室管理和适当研究行为的专门课程。该项目将侧重于FAAH抑制在治疗阿片依赖方面具有或可能具有治疗优势的机制。奖励阈值的变化被建立为随着海洛因的使用而增加，假设在存在FAAH抑制剂治疗的情况下是正常的。此外，在停药期间与阴性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，将在有无FAAH抑制剂治疗的情况下进行检查。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措施所证实。最后，基因靶向的FAAH缺陷大鼠的产生将使我们能够检查由于海洛因长期戒断而引起的应激相关基因的变化，以及FAAH在药物、线索和应激源存在的情况下对海洛因复发易感性的长期失活。结合起来，该项目将进一步加深对海洛因成瘾、作为一种重复压力形式的药物成瘾、内源性大麻素通过减少与药物相关的应激源和快感缺乏来打破药物滥用循环的作用的理解。

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.