GABA Drugs for Cannabis-Use Disorders: Initial Mechanistic Studies in Humans

用于治疗大麻使用障碍的 GABA 药物：人类初步机制研究

基本信息

批准号：
7564517
负责人：
Joshua Anthony Lile
金额：
$ 36.63万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7564517
关键词：
Admission activity Agonist Attenuated Baclofen Barbiturates Behavioral Benzodiazepine Receptor Benzodiazepines Cannabinoids Cannabis Cardiovascular system Clinical Data Clinical Research Controlled Clinical Trials Cues Data Dependence Development Diagnostic Diazepam Disease Dose Drug Interactions Drug Use Disorder Drug usage Elevation Foundations Future GABA Receptor Human Illicit Drugs Link Maintenance Measures Mediating Medication Management Memory Neurobiology Outcome Patients Persons Pharmaceutical Preparations Pharmacological Treatment Pharmacotherapy Physiological Physiology Population Procedures Psychomotor Performance Public Health Questionnaires Rate Receptor Activation Relapse Reporting Stimulus System Testing United States barbituric acid salt drug discrimination drug of abuse gamma-Aminobutyric Acid inhibitor/antagonist innovation memory process neurochemistry novel pre-clinical preclinical study receptor research study reuptake tiagabine

项目摘要

DESCRIPTION (provided by applicant): Cannabis remains the most commonly used illicit drug worldwide, including the United States. Not only does a relatively large percentage of the population report using cannabis, but like other drugs of abuse, a significant proportion of those persons use it habitually and meet diagnostic criteria for drug-use disorders. Moreover, cannabis-use disorders are associated with treatment admission and relapse rates comparable to other drugs of abuse perceived as more harmful. Despite the significant public health concern posed by cannabis use, there has been limited preclinical or clinical research that has focused explicitly on the identification and development of medications to treat cannabis-use disorders. Data from preclinical and clinical research suggest that agonist replacement treatment is an effective means to manage drug-use disorders, and that this strategy would be viable for cannabis-use disorders as well. The experiments proposed here represent the initial step of evaluating GABAergic drugs as potential "agonist-like" pharmacotherapies for cannabis-use disorders. GABA is being targeted because there is substantial overlap in the effects produced by cannabinoids and drugs acting at central GABAergic systems, and neuroanatomical, neurochemical and behavioral studies support a functional link between cannabinoid and GABAergic systems. The studies proposed here will test the ability of the selective GABA reuptake inhibitor tiagabine, the GABAA positive modulator diazepam and the GABAB agonist baclofen to enhance the behavioral and physiological effects of ?9-THC, thus examining the "agonist-like" profile of GABAergic drugs with varying mechanisms of action. The primary outcome for these experiments is the interoceptive cue produced by ?9-THC. The interoceptive effects of ?9-THC will be measured using the drug-discrimination procedure, which is a pharmacologically specific and sensitive means to characterize drugs and drug interactions. In addition, subjective effects questionnaires, psychomotor performance and memory tasks, and cardiovascular and thermal measures of physiology will be included to more fully assess the effects of ?9-THC alone and in combination with GABAergic compounds. The experiments proposed here are novel and innovative because there are very few studies in humans to have tested the effects of GABAergic drugs on cannabinoids. In addition, these studies are important for at least three reasons. First, and perhaps most importantly, the data generated from the proposed experiments will provide the direction and foundation for future studies aimed at the development of GABAergic treatments for cannabis-use disorders. Second, these data will provide valuable information regarding the neurobiology of the effects of cannabinoids in humans by examining the interactions between cannabinoid and GABAergic systems. Finally, these experiments will provide translational information regarding the extent to which the results from preclinical studies that have evaluated CB-GABA interactions generalize to humans. Public Health Relevance: Cannabis is the most commonly used illicit drug in the United States and its use is associated with rates of development of abuse and dependence, treatment admission and relapse that are comparable to other illicit drugs that are misperceived as more harmful. Currently there is no effective pharmacological treatment for cannabis-use disorders. The experiments proposed here represent the initial step of evaluating GABAergic drugs as potential pharmacotherapies by characterizing interactions between ?9-THC and the selective GABA reuptake inhibitor tiagabine, the GABAA positive modulator diazepam and the GABAB agonist baclofen.

描述（由申请人提供）：大麻仍然是包括美国在内的全球最常用的非法药物。不仅使用大麻的人口报告中相对较大的人口报告，而且像其他滥用药物一样，其中很大一部分人习惯地使用它并符合药物使用疾病的诊断标准。此外，使用大麻疾病与治疗入院和复发率有关，可与其他被认为更有害的虐待药物相当。尽管使用大麻对公共卫生的关注很大，但仍有有限的临床前或临床研究明确地集中在治疗大麻疾病的药物鉴定和开发上。临床前和临床研究的数据表明，激动剂替代治疗是管理药物疾病的有效手段，并且该策略也对大麻使用疾病也是可行的。此处提出的实验是评估GABA能药物作为大麻疾病的潜在“类似激动剂”的药物治疗的第一步。 GABA的目标是因为在中央Gabaergic系统中作用的大麻素和药物产生的作用存在实质性重叠，以及神经解剖学，神经化学和行为研究支持大麻素和Gabaergic Systems之间的功能联系。此处提出的研究将测试选择性GABA再摄取抑制剂tiagabine，Gabaa阳性调节剂地西epam和Gabab agonist baclofen增强？9-THC的行为和生理效应，从而研究了与varary机制的Gabaergic pressimiss的“激动剂样”的“激动剂样”曲线。这些实验的主要结果是由9-thc产生的感受性提示。 9-thc的互感影响将使用药物歧视程序测量，这是药理特异性且敏感的手段，以表征药物和药物相互作用。此外，将包括主观效果问卷，精神运动的表现和记忆任务以及生理学的心血管和热度量，以更全面地评估单独的9-THC的影响，并与GABAERGIC化合物结合使用。此处提出的实验是新颖和创新的，因为人类在人类中很少研究GABA能药物对大麻素的影响。此外，这些研究至少出于三个原因很重要。首先，也许最重要的是，提出的实验产生的数据将为未来的研究提供方向和基础，以开发用于大麻疾病的GABA能治疗。其次，这些数据将通过检查大麻素和GABA能系统之间的相互作用，提供有关大麻素对人类影响的神经生物学的宝贵信息。最后，这些实验将提供有关评估CB-GABA相互作用的临床前研究结果的转化信息。公共卫生相关性：大麻是美国最常用的非法药物，其使用与滥用和依赖，治疗疗法和复发的发展速度相关，这些药物与其他被误解为更加有害的非法药物相当。目前尚无对大麻疾病的有效药理治疗。此处提出的实验代表了通过表征“ 9-THC和选择性GABA再摄取抑制剂tiagabine，GABAA阳性调节剂白疗和Gabab agonist Baclofen之间的相互作用，则代表了评估GABA能药物作为潜在药物治疗的初步步骤。