Combined mGluR5 PET and fMRI imaging of Sex Differences during Cocaine Withdrawal

项目摘要 有令人信服的临床前，流行病学和临床证据表明，女性更容易受到 可卡因效应，包括奖励幅度和积极的主观效应，可卡因的发展速度 使用障碍（CUD）和可卡因戒断后的复发风险。临床前研究已经证明 雌二醇（激活）和孕酮（抑制）对行为和神经系统的相反作用 对可卡因的反应谷氨酸（Glu）系统在可卡因使用中起着核心作用，有助于 发展和维持规律的使用、戒断和禁欲后的恢复。重要的是， 最近的脑成像研究显示，在脑缺血期间，mGluR 5结合潜力（BPND）显著降低。 可卡因戒断然而，迄今为止，CUD人脑成像研究仅招募了男性受试者， 纳入的女性受试者太少，无法进行性别分析。拟议的研究将 研究可卡因戒断期间mGluR 5 BPND的性别差异作为性腺激素的函数， 可卡因使用障碍的女性和男性以及健康对照组。响应于 审查员担心，这项修订后的申请增加了功能磁共振成像扫描，以扩大检查性别差异， 在可卡因戒断过程中，与靶向谷氨酸系统平行激活的神经回路。fMRI 程序将包括静息状态功能连接扫描（rsFC）以及可卡因线索诱导的 事件相关扫描（CC）在可卡因戒断期间发生在受试者体内。我们特别增加了 因为众所周知，女性对渴望和其他相关影响更敏感， 可卡因的线索，在月经的卵泡期。我们将招募20名女性和20名男性非治疗患者 寻找CUD参与者在第1天，CUD受试者接受可卡因输注，完全正电子发射， 使用[18F]FPEB进行断层扫描（PET）成像以定量mGluR 5 BPND，然后进行rsFC和CC fMRI。妇女 将处于月经周期的黄体期。在为期15天的CRU停留期间，将采集血液用于 测量激素，并且受试者将完成戒断严重程度、渴望和情绪的测量。对 第15天，受试者将接受第二组[18F]FPEB PET和fMRI扫描。这一提议将是第一个 目的：描述女性和男性CUD患者的mGluR 5特征;检查mGluR 5与静息状态的关系 和可卡因提示大脑功能和可卡因戒断和渴望的关键行为措施。最 重要的是，将研究性激素在这些影响中的潜在作用。尽管三十多年来， 在研究中，没有有效的药物疗法被批准用于可卡因治疗。因此，有一个 迫切需要为药物开发确定新的神经递质靶点，并解决性别问题- 特殊的治疗需求。研究结果可能会为可卡因治疗提供个性化，性别特异性干预措施。

Project Summary There is compelling preclinical, epidemiological and clinical evidence of greater vulnerability in females for cocaine effects, including reward magnitude and positive subjective effects, rate of development of cocaine use disorder (CUD), and relapse risk following cocaine abstinence. Preclinical studies have demonstrated opposing effects of estradiol (activating) and progesterone (dampening) on behavioral and neurological responses to cocaine. The glutamate (Glu) system plays a central role in cocaine use, contributing to development and maintenance of regular use, withdrawal, and reinstatement following abstinence. Importantly, recent brain imaging studies have shown significant reductions in mGluR5 binding potential (BPND) during cocaine abstinence. To date, however, CUD human brain imaging studies have enrolled only male subjects or have included too few female subjects to permit analyses as a function of sex. The proposed research will examine sex differences in mGluR5 BPND during cocaine withdrawal as a function of gonadal hormones in women and men with cocaine use disorder and in a comparison group of healthy controls. In response to reviewer concerns, this revised application adds fMRI scans to broaden examination of sex differences in neurocircuitry that is activated in parallel with the targeted glutamate system during cocaine withdrawal. fMRI procedures will include both resting state functional connectivity scans (rsFC) as well as cocaine cue-induced event-related scans (CC) to occur within-subject during cocaine abstinence. We are specifically adding cueing procedures because it is known that women are more sensitive to craving and other associated effects of cocaine cues, during the follicular phase of menses. We will enroll 20 female and 20 male non-treatment seeking CUD participants. On day 1, CUD subjects undergo cocaine infusion, complete positron emission tomography (PET) imaging using [18F]FPEB to quantify mGluR5 BPND, followed by rsFC and CC fMRI. Women will be in the luteal phase of their menstrual cycle. During the 15-day CRU stay, bloods will be collected for measurement of hormones, and subjects will complete measures of withdrawal severity, craving and mood. On day 15, subjects will undergo a second set of [18F]FPEB PET and fMRI scans. This proposal will be the first to: characterize mGluR5 in women and men with CUD; examine the relationship of mGluR5 to resting state and cocaine cued brain function and to key behavioral measures of cocaine withdrawal and craving. Most importantly, the potential role of sex hormones in these effects will be studied. Despite over three decades of research, there are no efficacious pharmacotherapies approved for cocaine treatment. Thus, there is a pressing need to identify new neurotransmitter targets for medication development and to address gender- specific treatment needs. Findings may inform personalized, sex specific interventions for cocaine treatment.