Imaging the neurochemistry of negative reinforcement in cocaine abuse

描述(申请人提供)：治疗可卡因依赖最困难的方面之一是戒除一段时间后再次使用可卡因的倾向。虽然以前的研究主要集中在积极强化和复发方面，但最近的研究已经开始探索消极强化的神经生物学。在压力环境中使用药物可以缓解压力，从而起到负向强化作用。临床前研究表明，kappa受体的激活介导了应激诱导的可卡因寻找行为，而不是可卡因诱导的可卡因寻找行为，这表明kappa受体的激活对负性强化具有选择性。以前关于可卡因依赖的死后研究表明，kappa受体在这种疾病中没有调节。然而，由于无法在体内对这种受体进行成像，因此缺乏研究这种变化的行为意义的研究。在这项应用中，我们将使用新开发的kappa受体选择性PET放射性示踪剂[11C]GR103545来探索可卡因滥用中神经化学的这种变化。此外，鉴于强啡肽被认为可以密切调节纹状体的多巴胺传递，我们使用了货币激励延迟任务，它产生了纹状体的可重复激活，并已被证明与纹状体的多巴胺传递相关。因此，我们将首次比较可卡因滥用者和配对对照组的神经化学和纹状体功能的变化。此外，在可卡因滥用受试者中，我们将使用应激诱导的可卡因寻找行为的实验室模型来探索神经生物学和负性强化之间的相关性。我们还将包括一组可卡因滥用者，他们在启动剂量的可卡因后接受可卡因自我给药，以证明Kappa受体系统对应激诱导的可卡因寻找行为的特异性。这项应用的最后一个具体目标是在人类身上进行研究，这是一种有充分证据的临床前现象，在这种现象中，大量服用可卡因会显著增加强啡肽的水平。为了调查这一点，滥用可卡因的志愿者将参加狂欢可卡因自我管理会议。在这些疗程之后，将重复进行成像扫描和应激诱导的可卡因自我给药疗程，以调查大脑中强啡肽增加的影响。 公共卫生相关性：本申请中包含的研究的目标是通过重点研究大脑中的kappa受体/强啡肽系统来表征可卡因滥用中负强化的神经生物学特征。利用影像和行为研究，这项应用试图进一步加深我们对复发这一重要现象的理解。

DESCRIPTION (provided by applicant): One of the most difficult aspects of treating cocaine dependence is the propensity for relapse to cocaine use after a period of abstinence. While previous research has focused on positive reinforcement and relapse, recent studies have begun to explore the neurobiology of negative reinforcement. Drug use in setting of stress provides negative reinforcement by relieving the stress. Preclinical studies show that kappa receptor activation mediates stress-induced, but not cocaine-induced, cocaine- seeking behavior, suggesting that that kappa receptor activation is selective for negative reinforcement. Previous postmortem studies in cocaine dependence have shown that the kappa receptor is unregulated in this disorder. However, studies investigating the behavioral significance of this change have been lacking due to the inability to image this receptor in vivo. In this application, we will use the newly developed kappa receptor selective PET radiotracer [11C]GR103545 to explore this alteration in neurochemistry in cocaine abuse. In addition, given that dynorphin is known to closely regulate striatal dopamine transmission we use the Monetary Incentive Delay Task, which produces reproducible activation of the striatum, and has been shown to correlate with striatal dopamine transmission. Thus, we will compare alterations neurochemistry and striatal function in cocaine abusers and matched controls for the first time. Additionally, within the cocaine abusing subjects, we will use a laboratory model of stress-induced cocaine seeking behavior in order to explore the correlation between the neurobiology and negative reinforcement. We will also include a group of cocaine abusers who undergo cocaine self-administration sessions following a priming dose of cocaine, in order to demonstrate the specificity of the kappa receptor system for stress-induced cocaine seeking behavior. A final specific aim of this application is to investigate in humans, a well- documented preclinical phenomenon in which binge dosing of cocaine significantly increases dynorphin levels. To investigate this, the cocaine abusing volunteers will participate in binge cocaine self-administrations sessions. Following the sessions, the imaging scans and the stress-induced cocaine self-administration sessions will be repeated, in order to investigate the effect of increased dynorphin in the brain. PUBLIC HEALTH RELEVANCE: The goals of the studies included in this application are to characterize the neurobiology of negative reinforcement in cocaine abuse by focusing on the kappa receptor/dynorphin system in the brain. Using both imaging and behavioral studies, this application seeks to further our understanding this important phenomena in relapse.