GABA Function During Cocaine Abstinence

可卡因戒断期间 GABA 的功能

• 批准号: 8567361
• 负责人: SCOTT E LUKAS
• 金额: $ 18.67万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-15 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8567361
• 关键词: Abstinence; Address; Affect; Behavioral; Brain; Clinical; Clinical Research; Cocaine; Cocaine Dependence; Data; Drug Addiction; Drug Exposure; Effectiveness; Etiology; FDA approved; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; Funding; GABA Agents; Genetic Crossing Over; Goals; Homeostasis; Hour; Human; Image; Impaired cognition; Impairment; Individual; Investigation; Knowledge; Literature; Magnetic Resonance Spectroscopy; Measures; Medicine; National Institute of Drug Abuse; Nature; Neurobiology; Outcome; Performance; Pharmaceutical Preparations; Photic Stimulation; Play; Prefrontal Cortex; Process; Protons; Psychiatry; Psychotherapy; Readiness; Recovery; Relative (related person); Reporting; Research; Role; Signal Transduction; Staging; System; Testing; Time; TimeLine; Training; Visual Cortex; addiction; base; blood oxygen level dependent; cocaine exposure; cost; disorder later incidence prevention; effective therapy; experience; gamma-Aminobutyric Acid; improved; innovation; neuroimaging; neuropsychological; public health relevance; receptor; response; restoration; substance abuse treatment; success; tool; treatment center; treatment planning; treatment strategy; volunteer; zolpidem

DESCRIPTION (provided by applicant): This application seeks to challenge current approaches to treating drug dependence by investigating the idea of neurobiological "readiness for treatment". This notion is analogous to the behavioral stages of change conceptualized in the field of psychotherapy and already applied to substance abuse treatment, but here it refers to objective indicators of the brain's ability to respond to medication at a specific point during recovery. The proposed project will focus on the cocaine-GABA relationship as an exemplar because no FDA-approved pharmacotherapeutics exist for treating cocaine dependence, but a number of candidate medications targeting the GABA system are under investigation. While the strategy of boosting GABA activity pharmacologically is supported by a significant body of evidence implicating GABAergic dysfunction in the etiology of cocaine dependence, we believe its modest success to date is due to the one-size-fits-all approach that assumes cocaine-related GABAergic impairment is stable over the stages of recovery. We challenge this by asking, how do GABA levels change when the brain has an opportunity to readjust after drug exposure ceases? Also, how does the GABA baseline affect the brain's ability to respond to treatment with GABAergic medications? The primary goal of this project is to address these gaps in our knowledge that we believe represent barriers to treatment. To accomplish this goal, we will assess proton magnetic resonance spectroscopy (1H MRS) and blood oxygen level-dependent functional magnetic resonance imaging (BOLD fMRI) correlates of GABAergic function longitudinally during an incentivized abstinence period in non-treatment-seeking cocaine-dependent volunteers. The first aim will establish the timeline of cocaine abstinence-related changes in GABA levels by tracking GABA during active exposure and through both early and prolonged abstinence. The second aim will demonstrate the dynamic nature of GABAergic responsivity over the same time course by probing the system with a GABAergic drug challenge. Together, these aims will use neuroimaging as a tool to establish the cross- over point to "readiness for treatment". These objective indicators will improve our ability to plan treatment by permitting the clinician to predict the points at which an individual will be receptiv to a specific medication. Thus, one medication may be employed for abstinence initiation, and then once the brain has re-established GABAergic homeostasis, another medication can be used for relapse prevention. However, because not every treatment center has access to an imaging facility, a secondary goal is to evaluate the relationship between recovering GABA activity and cocaine-related cognitive impairments to determine the extent to which timed administration of a neuropsychological performance battery can predict GABAergic function. Our results will have the potential for high impact because the conceptual framework of brain "readiness for treatment" can be applied to drug dependence and psychiatry in general in order to provide a foundation for individualizing medicine.

描述（由申请人提供）：本申请旨在通过研究神经生物学“治疗准备”的想法来挑战目前治疗药物依赖的方法。这一概念类似于心理治疗领域中概念化的行为变化阶段，并已应用于药物滥用治疗，但在这里它指的是大脑在恢复期间特定时间点对药物反应能力的客观指标。拟议的项目将侧重于可卡因-GABA的关系作为一个范例，因为没有FDA批准的药物治疗存在用于治疗可卡因依赖，但一些候选药物针对GABA系统正在调查中。虽然促进GABA活性的策略得到了大量证据的支持，这些证据表明GABA能功能障碍与可卡因依赖的病因有关，但我们认为迄今为止的适度成功是由于一刀切的方法，该方法假设可卡因相关的GABA能损伤在恢复阶段是稳定的。我们提出了一个问题，即当大脑在药物暴露停止后有机会重新调整时，GABA水平如何变化？此外，GABA基线如何影响大脑对GABA能药物治疗的反应能力？该项目的主要目标是解决我们认为代表治疗障碍的知识差距。为了实现这一目标，我们将评估质子磁共振波谱（1H MRS）和血氧水平依赖性功能性磁共振成像（BOLD fMRI）的GABA能功能的相关性纵向在一个激励戒断期间在非寻求治疗的可卡因依赖志愿者。第一个目标是通过跟踪主动接触期间以及早期和长期戒断期间的GABA，建立与可卡因戒断相关的GABA水平变化的时间轴。第二个目标将通过用GABA能药物激发探测系统来证明GABA能反应性在同一时间过程中的动态性质。总之，这些目标将使用神经影像学作为一种工具，以建立交叉点，以“准备治疗”。这些客观的指标将提高我们的能力，规划治疗，允许临床医生预测的点，在这一点上，一个人将接受特定的药物。因此，一种药物可以用于禁欲启动，然后一旦大脑重新建立了GABA能稳态，另一种药物可以用于复发预防。然而，由于不是每个治疗中心都有成像设备，因此次要目标是评估恢复GABA活性和可卡因相关认知障碍之间的关系，以确定定时给予神经心理性能电池可以预测GABA能功能的程度。我们的研究结果将有可能产生很大的影响，因为大脑“准备治疗”的概念框架可以应用于药物依赖和精神病学，为个性化医疗提供基础。