GABA Function During Cocaine Abstinence

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”的概念来挑战目前治疗药物依赖的方法。这个概念类似于心理治疗领域的行为变化阶段概念，并已应用于药物滥用治疗，但这里它指的是大脑在恢复过程中某一特定时刻对药物反应能力的客观指标。拟议的项目将把重点放在可卡因与GABA的关系上，作为一个范例，因为目前还没有fda批准的治疗可卡因依赖的药物，但是一些针对GABA系统的候选药物正在研究中。虽然在药理学上提高GABA活性的策略得到了大量证据的支持，这些证据表明，可卡因依赖的病因中存在GABA能功能障碍，但我们认为，迄今为止，它的适度成功是由于一种通用的方法，即假设可卡因相关的GABA能损伤在恢复阶段是稳定的。我们挑战这个问题，当大脑在药物暴露停止后有机会重新调整时，GABA水平是如何变化的？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这些我们认为代表治疗障碍的知识差距。为了实现这一目标，我们将在非寻求治疗的可卡因依赖志愿者的激励戒断期间纵向评估质子磁共振波谱（1H MRS）和血氧水平依赖功能磁共振成像（BOLD fMRI）与gaba能功能的相关性。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水平，建立与可卡因戒断相关的GABA水平变化的时间表。第二个目标将通过用gabaergy药物挑战探测系统，在同一时间过程中证明gabaergy反应性的动态性质。总之，这些目标将利用神经影像学作为一种工具来建立交叉点，以“准备治疗”。这些客观指标将提高我们计划治疗的能力，使临床医生能够预测个体对特定药物的接受程度。因此，一种药物可以用于戒断开始，然后一旦大脑重新建立gaba能稳态，另一种药物可以用于预防复发。然而，由于不是每个治疗中心都有成像设备，第二个目标是评估GABA活性恢复与可卡因相关认知障碍之间的关系，以确定定时给药的神经心理性能电池可以预测GABA功能的程度。我们的研究结果可能会产生很大的影响，因为大脑“治疗准备”的概念框架可以应用于药物依赖和一般的精神病学，从而为个性化药物提供基础。

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.