A Novel Role of Interpeduncular Nucleus GLP-1Rs in Fentanyl Reinstatement

项目摘要： 致命的阿片类药物过量是美国可预防死亡的主要原因，到2021年， 超过60%的药物过量死亡与芬太尼及其类似物有关。虽然目前的药理学 阿片类药物使用障碍的治疗是有效的，耻辱和有限的获取使这些药物利用不足 复发率仍然很高。尽管非法使用芬太尼的流行， 研究芬太尼寻求的神经生物学机制。推进我们对 芬太尼寻求的神经回路可能有助于开发芬太尼使用的新治疗方法 减少芬太尼过量死亡。最近，我们发现，全身性给予 胰高血糖素样肽-1受体（GLP-1 R）激动剂Exendin-4（Ex-4）减弱芬太尼复吸，模型 复发。然而，Ex-4对芬太尼寻求的抑制作用的神经机制是 不清楚我们激动人心的初步研究表明，脚间核（IPN）中GLP-1 R的激活， 已知调节中脑边缘多巴胺系统的大脑区域足以减弱芬太尼寻求 雄性和雌性大鼠禁欲期间的行为。此外，我们还发现了μ阿片受体和GLP- 1 Rs表达于从IPN投射到被盖背外侧核（LDTg）的GABA能神经元上， 一个向腹侧被盖区发送投射的核团，在药物寻找和阿片类药物诱导的 奖励这些结果强调了可能介导GLP-1 R激动剂对以下细胞的抑制作用的神经回路： 寻找芬太尼然而，在芬太尼寻求行为期间，该回路的活动尚未被研究。 本提案的目的是确定急性芬太尼和Ex-4对GABA能神经活动的影响。 IPNàLDTg通路以及这种活性与芬太尼寻求行为之间的关系。探讨 GABA能IPNàLDTg投射在芬太尼复吸中的作用，Aim 1将使用体内钙成像 以表征芬太尼寻求行为期间GABA能IPN投射到LDTg的实时活性。 目的2将确定Ex-4药物治疗如何改变GABA能IPNALDTg投射的钙活性， 减少芬太尼的使用。成功完成这些目标将是未来学习的重要基础 研究寻找芬太尼的神经基础理想情况下，这项工作的结果将提出新的治疗方法， 芬太尼使用障碍的途径完成这项研究金将实现培训目标，扩大 赫尔曼女士在成瘾神经科学方面的技术专长，并促进她成为一名领先的 物质使用障碍的神经生物学研究员。

Project Summary: Fatal opioid overdose is a leading cause of preventable death in the United States, and in 2021 more than 60% of drug overdose deaths were associated with fentanyl and its analogs. While current pharmacological treatments for opioid use disorder are effective, stigma and limited access make these medications underutilized and rates of relapse are still high. Despite the prevalence of illicit fentanyl use, there are very few studies investigating the neurobiological mechanisms underlying fentanyl seeking. Advancing our understanding of the neural circuits underlying fentanyl seeking may facilitate the development of novel treatments for fentanyl use disorder and reduce fentanyl overdose deaths. Recently, we showed that systemic administration of the glucagon-like peptide-1 receptor (GLP-1R) agonist Exendin-4 (Ex-4) attenuates fentanyl reinstatement, a model of relapse. However, the neural mechanisms underlying the suppressive effects of Ex-4 on fentanyl seeking are unclear. Our exciting pilot studies demonstrate that activation of GLP-1Rs in the interpeduncular nucleus (IPN), a brain region known to regulate the mesolimbic dopamine system, is sufficient to attenuate fentanyl-seeking behavior during abstinence in male and female rats. Additionally, we discovered µ opioid receptors and GLP- 1Rs expressed on GABAergic neurons that project from the IPN to the laterodorsal tegmental nucleus (LDTg), a nucleus that sends projections to the VTA and plays an important role in drug seeking and opioid-induced reward. These results highlight a neural circuit that may mediate the suppressive effects of GLP-1R agonists on fentanyl seeking. However, the activity of this circuit during fentanyl-seeking behavior has not been investigated. The goal of this proposal is to determine the impact of acute fentanyl and Ex-4 on neural activity in the GABAergic IPNàLDTg pathway and the relationship between such activity and fentanyl-seeking behavior. To investigate the role of the GABAergic IPNàLDTg projection in fentanyl reinstatement, Aim 1 will use in vivo calcium imaging to characterize the real-time activity of GABAergic IPN projections to the LDTg during fentanyl-seeking behavior. Aim 2 will determine how Ex-4 pharmacotherapy alters calcium activity of GABAergic IPNàLDTg projections to reduce fentanyl seeking. Successful completion of these aims will be an important foundation for future studies investigating the neural basis of fentanyl seeking. Ideally, results from this work will suggest novel therapeutic avenues for fentanyl use disorder. Completion of this fellowship will achieve the training goals of expanding the technical expertise of Ms. Herman in addiction neuroscience and facilitate her career goal of becoming a leading researcher in the neurobiology of substance use disorders.