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，女性更容易患上 可卡因效应，包括奖励的大小和积极的主观效应，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。临床前研究表明 雌二醇和孕酮对行为和神经的对立作用 对可卡因的反应。谷氨酸(Glu)系统在可卡因的使用中起着核心作用，有助于 发展和维持正常使用、戒断和戒除后的恢复。重要的是 最近的脑成像研究表明，mGluR5结合电位(BPND)在 可卡因戒断。然而，到目前为止，CUD人脑成像研究只招募了男性受试者或 纳入的女性受试者太少，不能作为性别的函数进行分析。拟议的研究将 研究可卡因戒断过程中mGluR5 BPND的性别差异与性腺激素的关系 有可卡因使用障碍的女性和男性，以及健康对照的对照组。作为对.的回应 审查者关注的是，这个修订后的应用程序增加了fMRI扫描，以扩大对 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。功能磁共振成像 程序将包括静息状态功能连通性扫描(RsFC)以及可卡因线索诱导 事件相关扫描(CC)在可卡因戒断期间在受试者内进行。我们特别增加了提示 手术是因为众所周知，女性对欲望和其他相关影响更敏感。 可卡因暗示，在月经的卵泡期。我们将招收20名女性和20名男性非治疗者 寻找CUD参与者。在第一天，CUD受试者接受可卡因输注，完全正电子发射 使用[18F]FPEB对mGluR5 BPND进行断层扫描(PET)成像，然后进行rsFC和CC功能磁共振成像。女人 将处于月经周期的黄体期。在CRU停留15天期间，将采集血液用于 测量荷尔蒙，受试者将完成戒断严重程度、渴望和情绪的测量。在……上面 第15天，受试者将接受第二组[18F]FPEB PET和fMRI扫描。这项提议将是第一个 TO：研究男性和女性CUD患者mGluR5的特征；检查mGluR5与静息状态的关系 可卡因提示大脑功能，并对可卡因戒断和渴望的关键行为指标产生影响。多数 重要的是，性激素在这些影响中的潜在作用将被研究。尽管三十多年来 研究表明，目前尚无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- 具体的治疗需求。研究结果可能为可卡因治疗提供个性化的、针对性别的干预措施。

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.