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

脚间核 GLP-1R 在芬太尼恢复中的新作用

• 批准号: 10679175
• 负责人: Rachel Jaschik Herman
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679175
• 关键词: Abstinence; Acute; Agonist; Animal Model; Attenuated; Behavior; Brain; Brain region; Calcium; Cell Nucleus; Development; Disease; Enterobacteria phage P1 Cre recombinase; Epidemic; Exposure to; FOS gene; Fellowship; Female; Fentanyl; Fiber; Fiber Optics; Foundations; Future; GLP-I receptor; Goals; Implant; Injections; Measures; Mediating; Modeling; Morphine; Neurobiology; Neurons; Neuropeptides; Neurosciences; Opioid; Opioid Receptor; Overdose; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Photometry; Pilot Projects; Play; Prevalence; Public Health; Rat Transgene; Rattus; Relapse; Research Personnel; Rewards; Role; Saline; Self Administration; Substance Use Disorder; Technical Expertise; Testing; Time; Training; United States; Withdrawal; Work; addiction; analog; career; cell type; exenatide; fentanyl abuse; fentanyl overdose; fentanyl seeking; fentanyl self-administration; fentanyl use; gamma-Aminobutyric Acid; glucagon-like peptide 1; in vivo; in vivo calcium imaging; incretin hormone; insight; interpeduncular nucleus; male; mesolimbic system; neural; neural circuit; neurobiological mechanism; neuromechanism; novel; novel therapeutics; opioid mortality; opioid overdose; opioid use disorder; optical fiber; overdose death; prevent; preventable death; receptor; sensor; social stigma; synthetic opioid

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.

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，而在2021年则更多 超过60％的药物过量死亡与芬太尼及其类似物有关。而目前的药理 阿片类药物使用障碍的治疗方法有效，污名和有限的获取，使这些药物未被充分利用 继电器的速度仍然很高。尽管非法芬太尼使用率很少，但很少有研究 研究寻求芬太尼的神经生物学机制。促进我们对 寻求芬太尼基础的神经回路可能有助于开发新的芬太尼使用治疗方法 混乱并减少芬太尼过量死亡。最近，我们证明了系统的全身管理 胰高血糖素样肽-1受体（GLP-1R）激动剂Exendin-4（EX-4）减弱芬太尼恢复原状，一种模型 解脱。但是，EX-4对芬太尼寻求抑制作用的抑制作用的神经机制是 不清楚。我们令人兴奋的试点研究表明，插道核（IPN）中GLP-1R的激活， 已知调节中唇多巴胺系统的大脑区域足以减弱寻求芬太尼 男性和雌性大鼠戒酒期间的行为。此外，我们发现了µ阿片受体和GLP- 1RS在从IPN到后dodorsal技术核（LDTG）的GABA能神经元上表达，， 将项目发送到VTA并在吸毒和阿片类药物引起的毒品中起重要作用的核 报酬。这些结果突出了一种神经回路，可能介导GLP-1R激动剂对 寻求芬太尼。但是，尚未研究该电路在寻求芬太尼的行为过程中的活性。 该提案的目的是确定急性芬太尼和EX-4对GABA能中神经活动的影响 IPNàLDTG途径以及此类活动与寻求芬太尼的行为之间的关系。调查 GABA能IPNàLDTG投影在芬太尼恢复原状的作用，AIM 1将在体内钙成像中使用 在寻求芬太尼的行为期间，表征GABA能IPN项目对LDTG的实时活动。 AIM 2将决定EX-4药物疗法如何改变GABA能IPnàldtg项目的钙活性 减少寻求芬太尼。这些目标的成功完成将是未来研究的重要基础 研究寻求芬太尼的神经基础。理想情况下，这项工作的结果将暗示新的治疗 芬太尼使用障碍的途径。该奖学金的完成将实现扩展的培训目标 赫尔曼女士在成瘾神经科学方面的技术专长，并促进了她成为领先的职业目标 药物使用障碍神经生物学的研究人员。