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“阿片类药物使用导致问题的问题模式 或苦恼”。2019年，超过36，000人过量服用合成阿片类药物，包括芬太尼， COVID-19大流行，过量死亡增加了30%。1，2目前OUD的治疗方法 包括治疗和药物辅助治疗（MAT），如美沙酮、丁丙诺啡， 纳洛酮。纳洛酮的依从率低，使用美沙酮存在耻辱感 和丁丙诺啡，因为它们是用于治疗OUD的阿片类药物。因此，获得这些药物的机会有限， 复吸率仍然很高。3 - 6，46复吸往往是由戒断和戒断引起的，我们假设， 因此，当对流体的需求被水满足时，例如，对药物的需求（即，退出）， 药因此，我们进一步假设，胰高血糖素样肽-1（GLP-1），一种饱腹感药物，可能是 用于减少OUD啮齿动物模型中的药物寻求和服用。作为支持，GLP-1靶向治疗是 有效降低啮齿动物模型对许多滥用物质的反应。8，55 - 56，72此外，我们发现 GLP-1受体激动剂（GLP-1 RA）可以减少海洛因自我给药，线索诱导的海洛因寻找， 和药物诱导的海洛因寻求复发。9，24 GLP-1 RA也可减少羟考酮的服用和寻求。15 最后，我们的初步数据表明，GLP-1 RA不仅可以减少线索和药物诱导的寻求， 海洛因，但也包括芬太尼（Urbanik等人，正在筹备中）。这一结论与最近的一份报告一致。 芬太尼导致大多数阿片类药物过量1，关键是我们要了解大脑中 芬太尼的作用以及GLP-1 RA治疗如何减轻这些作用。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。为了我们的啮齿动物 模型，我们将利用一个扩展的获取药物自我管理范例。22我们预测：（1）与 其他药物滥用测试，16，22-23一半的大鼠测试将是高药物接受者，这些大鼠将有较高的 线索诱导的寻求和GLP-1“饱腹感”通路的更大抑制以及奖励的更大激活 与低芬太尼服用者/寻求者相比。(2)芬太尼摄入，芬太尼寻求，大脑激活 GLP-1 RA利拉鲁肽治疗将减弱基因表达。(3)保护 GLP-1 R给药将阻断GLP-1 RA给药对行为和大脑的影响 将毒蜥外泌肽-9（Ex-9）拮抗剂直接注入外侧下丘脑。这些假设将被测试， 三个具体目标。如果我们的假设得到支持，我们将确定最脆弱的芬太尼 采取和寻找大鼠，通过GLP-1 RA治疗将这些受试者从芬太尼寻求中解救出来， 芬太尼，特别是在最脆弱的，抑制GLP-1“饱腹感”途径，并激活 奖励/寻求底物，并暗示GLP-1受体在外侧下丘脑- a 关键性地参与体内平衡和动机行为。

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.