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在一段时间的戒断后，有重新使用可卡因的倾向。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。在压力环境下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，而不是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死后研究表明，kappa受体在这种疾病中是不受调节的。然而，由于无法在体内对这种受体成像，研究这种变化的行为意义一直缺乏。在本应用中，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改变。此外，鉴于我们已经知道dynorphin与纹状体多巴胺传递密切相关，我们使用了货币激励延迟任务，该任务可产生纹状体的可重复激活，并已被证明与纹状体多巴胺传递相关。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变化。此外，在可卡因滥用者中，我们将使用压力诱导的可卡因寻求行为的实验室模型，以探索神经生物学与负强化之间的相关性。我们还将包括一组可卡因滥用者，他们在可卡因启动剂量后进行可卡因自我给药，以证明kappa受体系统对压力诱导的可卡因寻求行为的特异性。本应用程序的最后一个具体目的是研究在人类中，一种有充分记录的临床前现象，在这种现象中，大量服用可卡因会显著增加肌啡水平。为了调查这一点，可卡因滥用志愿者将参加狂欢可卡因自我管理会议。疗程结束后，成像扫描和压力诱导的可卡因自我服用疗程将重复进行，以研究大脑中肌啡增加的效果。

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.