Treatment of Opiate Dependence through Inhibition of Fatty Acid Amide Hydrolase

描述（由申请人提供）：该职业发展奖提案（通过脂肪酸酰胺水解酶抑制剂治疗阿片类药物依赖）建立在候选人之前的培训基础上，在通过抑制内源性大麻素降解酶增强其张力的行为影响领域，以及在阿片类药物自我给药和依赖模型领域。本提案的目的是检查和跟踪候选人产生的数据，表明慢性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，在海洛因自我给药模型中减弱依赖的进展，同时也减弱血清应激激素皮质酮水平的增加。为了有效地确定这些现象背后的机制和神经生物学原理，需要通过颅内自我刺激来检查动物在海洛因使用过程中的奖励状态。此外，学习生化技术，以有效地描述由于海洛因滥用而发生的神经变化，以及FAAH抑制所逆转的神经变化，将使我们更好地了解大脑区域和适应，这些区域和适应对防止海洛因依赖的进展至关重要。将采用的生化测量包括：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化测量领域的专家Benjamin Cravatt博士的指导下，以及George Koob博士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线，以证明奖励和压力在内源性大麻素系统对抗阿片成瘾的效用中所起的作用。斯克里普斯研究所的环境也将被用来提供培训，以提高候选人作为独立研究者的职业准备，包括有效的实验室管理和适当的研究行为的专业课程。该项目将重点关注FAAH抑制在治疗阿片类药物依赖方面具有或可能具有治疗优势的机制。奖赏阈值的变化被认为随着海洛因的使用而增加，假设在FAAH抑制剂治疗的存在下是正常化的。此外，在有和没有使用FAAH抑制剂治疗的情况下，将检查停药期间与负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。这些生化变化将通过海洛因戒断引起的焦虑和抑郁样行为的测量来证实。最后，基因靶向FAAH缺陷大鼠的产生将允许检查由于长期海洛因戒断引起的压力相关基因的变化，以及在药物、线索和压力源存在下FAAH长期失活对海洛因复发易感性的影响。综合起来，该项目将进一步加深对海洛因成瘾的科学认识，毒瘾是一种反复的压力，内源性大麻素通过减少与药物有关的压力源和快感缺乏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.