Imaging the neurochemistry of negative reinforcement in cocaine abuse

描述（由申请人提供）：治疗可卡因依赖最困难的方面之一是戒断一段时间后可卡因使用复发的倾向。虽然以前的研究主要集中在正强化和复发，但最近的研究已经开始探索负强化的神经生物学。在设置压力时使用药物通过缓解压力提供负强化。临床前研究表明，kappa受体激活介导应激诱导的可卡因寻求行为，但不介导可卡因诱导的可卡因寻求行为，这表明kappa受体激活对负强化具有选择性。先前对可卡因依赖的尸检研究表明，在这种疾病中κ受体是不受调节的。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。在本申请中，我们将使用新开发的κ受体选择性PET放射性示踪剂[11 C] GR 103545来探索可卡因滥用中神经化学的这种改变。此外，鉴于强啡肽已知密切调节纹状体多巴胺的传输，我们使用货币激励延迟任务，它产生可再现的纹状体激活，并已被证明与纹状体多巴胺传输相关。因此，我们将首次比较可卡因滥用者和匹配对照组的神经化学和纹状体功能的改变。此外，在可卡因滥用者中，我们将使用应激诱导的可卡因寻求行为的实验室模型，以探讨神经生物学和负强化之间的相关性。我们还将包括一组可卡因滥用者，他们在可卡因引发剂量后进行可卡因自我给药，以证明压力诱导的可卡因寻求行为的κ受体系统的特异性。本申请的最后一个具体目的是在人类中研究一种有充分记录的临床前现象，其中可卡因的过量给药显著增加强啡肽水平。为了调查这一点，滥用可卡因的志愿者将参加可卡因自我管理会议。在这些阶段之后，将重复成像扫描和应激诱导的可卡因自我给药阶段，以研究大脑中强啡肽增加的影响。 公共卫生相关性：本申请中包括的研究的目标是通过关注大脑中的κ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。使用成像和行为研究，该应用程序旨在进一步了解复发中的这一重要现象。

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.