Fentanyl Addiction: Individual Differences, Neural Circuitry, and Treatment with a GLP-1 Receptor Agonist

项目摘要 阿片类药物使用障碍(OUD)在DSM-V中被定义为“导致问题的阿片类药物使用问题模式 或遇险“。2019年，超过3.6万人过量服用包括芬太尼在内的合成阿片类药物， 新冠肺炎大流行以来，过量服药死亡人数增加了30%。1、2目前治疗OUD的方法 包括治疗和药物辅助治疗(MAT)，如美沙酮、丁丙诺啡和 纳曲酮。纳曲酮的依从率很低，而且使用美沙酮会带来耻辱。 丁丙诺啡，因为它们是用来治疗OUD的阿片类药物。因此，获得这些药物的机会有限，而且会复发。 3-6，46复发通常是由停药引起的，我们假设，停药是一种需要 因此，例如，由于水满足了对液体的需求，对药物(即戒断)的需求通过以下方式来满足 毒品。据此，我们进一步推测，一种饱腹症药物--胰高血糖素样肽-1(GLP-1) 用于减少OUD啮齿动物模型的寻药和吸食。在支持方面，GLP-1靶向治疗是 在啮齿动物模型中有效地降低了对许多滥用物质的反应。 GLP-1受体激动剂(GLP-1RAs)可减少海洛因自我给药，提示诱导海洛因寻求， 和药物诱导的海洛因寻找的恢复。9，24 GLP-1RA还减少羟考酮的摄入和寻找 最后，我们的初步数据表明，GLP-1RA不仅可以减少线索和药物诱导的寻求 海洛因，但芬太尼也(Urbanik等人，正在准备中)。这一发现与最近的一份报告一致。 芬太尼是导致大部分阿片类药物过量的原因1，关键是我们要了解大脑中的哪个部位 芬太尼的作用以及GLP-1RA治疗如何减轻这些影响。在这里，我们将使用啮齿动物 模型、光片显微镜、qRT-PCR和药理学来解决这些问题。对于我们的啮齿动物来说 22我们预测：(1)与 其他药物滥用测试，16，22-23接受测试的大鼠中有一半将是高吸毒者，这些大鼠将有更高的 线索诱导的寻求和对GLP-1“饱足感”通路的更大抑制和对奖赏的更大激活 底物与低芬太尼接受者/寻求者的比较。(2)芬太尼摄取、芬太尼寻求、脑激活 GLP-1RA、利拉鲁肽的治疗将减弱GLP-1RA的基因表达。(3)保护性 GLP-1R可阻断GLP-1RA对行为和脑的影响 拮抗剂exendin-9(Ex-9)，直接进入下丘脑外侧。这些假设将在以下方面得到检验 三个具体目标。如果我们的假设得到支持，我们将确定芬太尼中最脆弱的 服用并寻找老鼠，通过GLP-1RA治疗将这些受试者从寻求芬太尼的过程中解救出来，经验证 芬太尼，特别是在最脆弱的患者中，抑制GLP-1的饱腹感途径，并激活 奖赏/寻找底物，并暗示GLP-1受体在外侧下丘脑-a中起关键作用 与动态平衡和动机行为密切相关的结构。

Project Summary Opioid use disorder (OUD) is defined in the DSM-V as a “problematic pattern of opioid use leading to problems or distress”. More than 36,000 people overdosed on synthetic opioids including fentanyl in 2019 and, with the COVID-19 pandemic, there has been a 30% increase in overdose deaths.1,2 Current treatments for OUD include therapy and medication-assisted treatments (MATs) such as methadone, buprenorphine, and naltrexone. Naltrexone has low compliance rates and there is stigma associated with the use of methadone and buprenorphine, as they are opioids used to treat OUD. Access to these drugs, then, is limited, and relapse rates remain high.3-6,46 Relapse often is precipitated by withdrawal and withdrawal, we hypothesize, is a need state.7 Thus, as the need for fluid is sated by water, for example, the need for drug (i.e., withdrawal) is sated by drug. In accordance, we further hypothesized that glucagon-like peptide-1 (GLP-1), a satiety drug, could be utilized to reduce drug seeking and taking in rodent models of OUD. In support, GLP-1 targeted treatments are effective in reducing responding for many substances of abuse in rodent models.8,55-56,72 Additionally, we found that GLP-1 receptor agonists (GLP-1RAs) can reduce heroin self-administration, cue-induced heroin seeking, and drug-induced reinstatement of heroin seeking.9,24 GLP-1RAs also reduce oxycodone taking and seeking.15 Finally, our preliminary data suggest that a GLP-1RA can reduce cue- and drug-induced seeking of not only heroin, but fentanyl as well (Urbanik et al., in preparation). This finding is consistent with a recent report.13 With fentanyl contributing to the majority of opioid overdoses1, it is critical that we understand where in the brain fentanyl is acting and how treatment with a GLP-1RA might mitigate these effects. Here we will use rodent models, light sheet microscopy, qRT-PCR, and pharmacology to address these questions. For our rodent model, we will utilize an extended access drug self-administration paradigm.22 We predict that: (1) As with other drugs of abuse tested,16,22-23 half of the rats tested will be high drug takers and these rats will have higher cue-induced seeking and greater inhibition of the GLP-1 ‘satiety’ pathway and greater activation of reward substrates compared to low fentanyl taker/seekers. (2) Fentanyl intake, fentanyl seeking, brain activation patterns, and gene expression will be attenuated by treatment with the GLP-1RA, liraglutide. (3) The protective effects of GLP-1RA treatment on behavior and brain will be blocked by the administration of the GLP-1R antagonist, exendin-9 (Ex-9), directly into the lateral hypothalamus. These hypotheses will be tested across three specific aims. If our hypotheses are supported, we will have identified the most vulnerable of fentanyl taking and seeking rats, rescued these subjects from fentanyl seeking via treatment with a GLP-1RA, verified that fentanyl, particularly in the most vulnerable, inhibits the GLP-1 ‘satiety’ pathway and activates reward/seeking substrates, and implicated a key role for GLP-1 receptors in the lateral hypothalamus – a structure critically involved in homeostasis and motivated behavior.