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.

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