Understanding dynorphin and dopamine dynamics during fentanyl exposure

了解芬太尼暴露期间强啡肽和多巴胺的动态

• 批准号: 10449989
• 负责人: Sineadh Margaret Conway
• 金额: $ 6.98万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449989
• 关键词: Acute; Affect; Affective; Americas; Automobile Driving; Behavior; Brain region; COVID-19 pandemic; Cells; Chemosensitization; Chronic; Collaborations; Critical Thinking; Data; Disease; Dopamine; Dorsal; Drug Exposure; Dynorphins; Education; Fellowship; Fentanyl; Funding; Goals; High Prevalence; Measurement; Mediating; Messenger RNA; Microdialysis; Missouri; Motivation; Negative Valence; Neurons; Neuropeptides; Neurosciences; Neurosciences Research; Nucleus Accumbens; Pain; Peptides; Periodicity; Persons; Pharmaceutical Preparations; Positive Valence; Process; Proteins; Receptor Activation; Receptor Signaling; Regulation; Research; Research Personnel; Rewards; Role; Scanning; Signal Transduction; System; Testing; Time; Training; Translating; United States; Universities; Up-Regulation; Ventral Tegmental Area; Washington; Work; addiction; base; career development; drug of abuse; endogenous opioids; in vivo; kappa opioid receptors; liquid chromatography mass spectrometry; medical schools; multidisciplinary; nano-liquid chromatography; negative affect; neurotransmission; novel; opioid epidemic; opioid overdose; opioid use disorder; optogenetics; overdose death; preference; recruit; response; success; synthetic opioid; transmission process

PROJECT SUMMARY/ABSTRACT The U.S. is currently amidst an opioid epidemic and the rise of illicitly manufactured synthetic opioids like fentanyl is largely responsible for the tripling of overdose deaths. In order to better understand illicit fentanyl use and addiction, we must develop a better understanding of endogenous opioid function. Upregulation of the kappa opioid receptor (KOR) system and its endogenous neuropeptide dynorphin is implicated in disorders of addiction and pain. Activation of KORs, specifically in brain regions enriched with dopamine (nucleus accumbens, NAc, and ventral tegmental area, VTA), produces negative affective states and decreases motivation. However, our recent work along with others has shown that the function of the dynorphin/KOR system in the NAc shell is more nuanced. We have shown that photostimulation of dynorphinergic neurons in the ventral NAc shell drives aversive-like responses and dynorphin release whereas photostimulation of dynorphinergic neurons in the dorsal NAc shell drives reward-like behavior and dynorphin release, A limited understanding of the precise role of dynorphin in drug exposure is in part due to the lack of reliable in vivo measurements of released dynorphin levels. The goal of this proposal is to determine whether dynorphin release is recruited during acute fentanyl exposure in distinct subregions of the NAc and investigate which dynorphinergic projections are critical modulators of affect and fentanyl-induced dopamine release. Dynorphin/KORs are upregulated in the NAc following compulsive drug taking, as shown by increases in mRNA and protein levels. [[However, it is not known if dynorphin is recruited following acute drug exposure and whether this translates to an increase in dynorphin release. In Aim 1, I will directly test the hypothesis that dorsal and ventral NAc shell dynorphin release is differentially activated following acute fentanyl exposure using in vivo microdialysis and voltammetry.]] Although KOR-mediated dopamine suppression is largely attributed to direct action of KORs on dopamine terminals in the NAc, KORs in the VTA also act as a key regulator of affective behaviors and neurotransmission. Still, it is unclear whether dynorphinergic projections from the NAc to the VTA have a distinct role in modulating affect and drug evoked dopamine release. [[ In Aim 2, I will test the hypothesis that distinct dynorphin-expressing neuronal projections from the NAc to the VTA transmit positive and negative valence signals while also regulating fentanyl- induced dopamine release in a biphasic manner using optogenetics, real-time place testing, and fast-scan cyclic voltammetry. Once we understand how dynorphin signaling is recruited during acute fentanyl exposure and how this recruitment modulates fentanyl evoked dopamine release, we can then begin to investigate dynorphin and dopamine dynamics during chronic contingent fentanyl exposure and identify new targets for safe and effective mitigation of illicit fentanyl use and addiction.]] The success of this multidisciplinary fellowship training plan, which incorporates activities to expand my scientific and career development, will be facilitated by the exemplary opportunities in research, collaboration, and education provided by Washington University School of Medicine.

项目摘要/摘要 美国目前正处于阿片类药物流行和非法制造的合成阿片类药物如芬太尼的崛起之中 在很大程度上造成了服药过量死亡人数的三倍。为了更好地了解芬太尼的非法使用和 上瘾后，我们必须更好地了解内源性阿片类药物的功能。Kappa基因的上调 阿片受体系统及其内源性神经肽强啡肽与成瘾障碍的关系 和痛苦。Kors的激活，特别是在富含多巴胺的大脑区域(伏隔核，NAC， 和腹侧被盖区(VTA)，会产生消极的情绪状态，降低动力。然而，我们的 最近与其他研究一起表明，强啡肽/KOR系统在NAC壳中的功能更多 细微差别。我们已经证明，在NAc壳驱动的腹侧，强啡肽能神经元的光刺激 背侧强啡肽能神经元的厌恶反应和强啡肽释放及光刺激 NAC壳驱动奖赏样行为和强啡肽释放，对NAC的确切作用的理解有限 强啡肽在药物暴露中的部分原因是缺乏可靠的体内释放的强啡肽测量结果 级别。这项建议的目标是确定在急性芬太尼期间是否招募强啡肽的释放 暴露于NAC的不同亚区，并调查哪些强啡肽能投射是关键的 影响调节剂和芬太尼诱导的多巴胺释放。强啡肽/KRs在NAC中上调 在强制服药后，表现为信使核糖核酸和蛋白质水平升高。[[然而，还不知道 如果强啡肽在急性药物暴露后被招募，这是否会转化为强啡肽的增加 放手。在目标1中，我将直接测试背侧和腹侧NAc壳强啡肽释放是 使用体内微渗析和伏安法检测急性芬太尼暴露后的差异激活。]]虽然 KOR介导的多巴胺抑制很大程度上归因于KOR对多巴胺终末的直接作用。 VTA内的NAC、KRs也是情感行为和神经传递的关键调节因子。不过，目前还不清楚 从NAC到VTA的强啡肽能投射在调节情感和药物方面是否有不同的作用 引发了多巴胺的释放。[在目标2中，我将测试不同的强啡肽表达神经元的假设 从NAC到VTA的投射传递正价和负价信号，同时也调节芬太尼- 利用光遗传学、实时定位测试和快速扫描循环以双相方式诱导多巴胺释放 伏安法。一旦我们了解了在急性芬太尼暴露期间强啡肽信号是如何被招募的，以及如何 这种募集调节芬太尼引起的多巴胺释放，然后我们可以开始研究强啡肽和 慢性偶发芬太尼暴露期间的多巴胺动态和确定安全有效的新靶点 减少非法使用芬太尼和成瘾。]]这项多学科奖学金培训计划的成功， 融入了扩展我的科学和职业发展的活动，将由模范促进 华盛顿大学医学院提供的研究、合作和教育机会。