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：
9492964
负责人：
Joel Evan Schlosburg
金额：
$ 24.59万
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/9492964
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 Dependency 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 Opiates Opioid Pathway interactions Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Phenotype 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 Self-Administered 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 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的抑制剂治疗鸦片依赖性）建立在先前对候选者的培训的基础上，在抑制其降解性酶以及阿片类依赖性和依赖性模型中，通过抑制内源性大麻素张力来增强内源性大麻素的行为效果。该提案的目的是检查和跟进候选人产生的数据，该数据表明慢性抑制脂肪酸酰胺水解酶（FAAH）是负责降解内源性纳法胺的主要酶，使海洛蛋白自动化模型中的依赖性在serium级别上增加了依赖的依赖性，同时又会增加了压力。为了有效地确定这些现象的基础机制和神经生物学，将需要训练以检查动物的奖励状态，在使用海洛因的过程中，使用颅内自我刺激。此外，学习生化技术需要有效地表征由于海洛因滥用而发生的神经系统变化，而这种变化是由于FAAH抑制而逆转的，这将使人们对大脑区域和适应性的了解和适应性对防止海洛因依赖的进展至关重要。将要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。在本杰明·克拉瓦特（Benjamin Cravatt）博士的指导下，本杰明·克拉瓦特（Benjamin Cravatt）是内源性大麻素活动的生化量度衡量领域的专家，以及通过支持乔治·科布（George Koob）博士提供的毒品滥用相关行为模型的专业知识，候选人将能够整合融合的证据，以奖励与内牛素型的融合和压力相关的角色。 Scripps研究所环境还将用于提供培训，以增强候选人作为独立研究者职业的准备，包括有效的实验室管理和适当研究行为的专业课程。该项目将集中于法族人抑制作用或有可能在治疗阿片类药物依赖性方面有利的机制。假设在FAAH抑制剂治疗的存在下，奖励阈值的变化被确定为随着海洛因的使用而增加。此外，在存在和不接受FAAH抑制剂治疗的情况下，将检查与药物戒断期间与阴性状态下的生化变化，以CRF和糖皮质激素受体表达的变化为例。然后，这些生化变化将通过海洛因戒断引起的焦虑和抑郁症状行为的措施来证实。最后，因遗传靶向法族的大鼠的产生将允许检查由于持久的海洛因戒断而引起的与压力相关的基因的变化，以及在存在药物，提示和压力因子的存在下对海洛因复发敏感性的长期FAAH失活。该项目结合在一起，将进一步了解有关海洛因成瘾的理解，药物成瘾作为反复压力的一种形式，内源性大麻素对通过减少药物相关压力源和抗抗激素的作用来打破药物滥用周期的作用。