Treatment of Opiate Dependence through Inhibition of Fatty Acid Amide Hydrolase

通过抑制脂肪酸酰胺水解酶治疗阿片依赖

基本信息

批准号：
9757744
负责人：
Joel Evan Schlosburg
金额：
$ 24.63万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9757744
关键词：
2-arachidonylglycerol Abstinence Acute Agonist Amides Amygdaloid structure Anhedonia Animals Anxiety Area Auditory Behavior Behavioral Behavioral Model Biochemical Biological Products Brain Brain region Breeding CNR1 gene CNR2 gene Cannabinoids Catalysis Chronic Chronic stress Corticosterone Corticotropin-Releasing Hormone Receptors Cues Data Dependence Dose Drug Addiction Drug abuse Endocannabinoids Environment Enzymes Extinction (Psychology)FAAH inhibitor Fatty Acids Feedback Gene Expression Generations Genes Glucocorticoid Receptor Glucocorticoids Heroin Heroin Abuse Heroin Dependence Hormones Hypothalamic structure Infusion procedures Intake K-Series Research Career Programs Knock-out Knockout Mice Learning Literature Measures Mediating Modeling Monoacylglycerol Lipases Motivation Motor Mus Negative Reinforcements Neurobiology Neurologic Nociception Nucleus Accumbens Opiate Addiction Opioid Pathway interactions Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Phenotype Physical Dependence Play Predisposition Process Proteins Quantitative Reverse Transcriptase PCR Rattus Readiness Relapse Research Research Institute Research Personnel Rewards Rodent Role Sampling Science Self Administration Self Stimulation Serine Hydrolase Serum Stress System TRPV1 gene Techniques Testing Therapeutic Tissues Training Transgenic Organisms Western Blotting Withdrawal activity-based protein profiling anandamide anxiety-like behavior base biological adaptation to stress cannabinoid receptor career depressive symptoms drug withdrawal endocannabinoid signaling endogenous cannabinoid system enzyme activity fatty acid amide hydrolase follow-up heroin use inhibitor/antagonist locus ceruleus structure negative affect opioid abuse opioid use opioid withdrawal prevent public health relevance receptor receptor expression response stressor transcription activator-like effector nucleases

项目摘要

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.

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依赖）建立在候选人之前的培训基础上，在通过抑制其降解酶来增强内源性大麻素张力的行为影响领域，以及阿片类药物自我管理和依赖性模型领域。该提案的目的是检查和跟踪候选者产生的数据，这些数据表明，脂肪酸酰胺水解酶（FAAH）（负责降解内源性大麻素 anandamide 的主要酶）的长期抑制可减缓海洛因自我依赖性的进展-给药模型同时还抑制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，需要进行培训，以使用颅内自我刺激来检查海洛因使用过程中动物的奖励状态。此外，学习有效表征因海洛因滥用而发生的神经系统变化以及通过 FAAH 抑制所逆转的神经系统变化所需的生化技术，将有助于更好地了解对于防止海洛因依赖进展至关重要的大脑区域和适应。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，以及在 George Koob 博士的支持下提供的药物滥用相关行为模型的专业知识，候选人将能够整合一系列证据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方面发挥的作用。斯克里普斯研究所的环境还将用于提供培训，以增强候选人作为独立研究者的职业准备，包括有效实验室管理和适当研究行为的专门课程。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。奖励阈值的变化随着海洛因的使用而增加，假设在 FAAH 抑制剂治疗存在时会正常化。此外，在存在和不存在FAAH抑制剂治疗的情况下，将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。然后，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得到证实。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而导致的应激相关基因的变化，以及长期FAAH失活对海洛因复发易感性的影响。和压力源。结合起来，该项目将进一步加深对海洛因成瘾、药物成瘾作为一种反复压力的形式、内源性大麻素通过减少药物相关压力源和快感缺乏来打破药物滥用循环的作用的科学理解。