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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要：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 年会有更多超过 60% 的药物过量死亡与芬太尼及其类似物有关，而目前的药理学。阿片类药物使用障碍的治疗是有效的，但耻辱和有限的获取使这些药物未被充分利用尽管非法使用芬太尼很普遍，但复发率仍然很高。研究芬太尼寻求背后的神经生物学机制，增进我们对芬太尼寻求的理解。芬太尼寻求背后的神经回路可能有助于开发芬太尼使用的新疗法最近，我们证明了芬太尼的全身给药。胰高血糖素样肽 1 受体 (GLP-1R) 激动剂 Exendin-4 (Ex-4) 减弱芬太尼恢复模型然而，Ex-4 对芬太尼寻求抑制作用的神经机制是我们激动人心的初步研究表明，脚间核 (IPN) 中 GLP-1R 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此外，我们还发现了μ阿片受体和GLP-。 1Rs 在从 IPN 投射到背侧被盖核 (LDTg) 的 GABA 能神经元上表达，向 VTA 发送投射信号的细胞核，在药物寻找和阿片类药物诱导中发挥重要作用这些结果强调了可能介导 GLP-1R 激动剂的抑制作用的神经回路。然而，芬太尼寻求行为期间该电路的活动尚未得到研究。该提案的目标是确定急性芬太尼和 Ex-4 对 GABA 能神经活动的影响 IPNàLDTg 通路以及此类活动与芬太尼寻求行为之间的关系。 GABAergic IPNàLDTg 投影在芬太尼恢复中的作用，目标 1 将使用体内钙成像表征芬太尼寻求行为期间 GABA 能 IPN 投射到 LDTg 的实时活动。目标 2 将确定 Ex-4 药物疗法如何改变 GABAergic IPNàLDTg 预测的钙活性减少芬太尼寻求的成功完成这些目标将成为未来研究的重要基础。理想情况下，研究芬太尼寻求的神经基础将提出新的治疗方法。完成该研究金将实现扩大芬太尼使用障碍的培训目标。赫尔曼女士在成瘾神经科学方面的技术专业知识，有助于她成为领先的职业目标物质使用障碍神经生物学研究员。