Leveraging Functional Selectivity in the Neurotensin Receptor 1-Mediated Treatment of Addiction

翻译后摘要：阿片类药物和精神兴奋剂成瘾是大的和日益增长的公共卫生问题， 现有治疗方法无法充分控制。本提案的目标直接针对这一未得到满足的问题， 临床需要，因为它包括一种新的抗成瘾治疗策略的评价。的一个共同特征 成瘾性药物的一个重要特征是它们能够诱导中脑边缘多巴胺系统的不适当激活。恢复 多巴胺信号稳态可以通过靶向G蛋白偶联受体（GPCR）来实现。 神经降压素受体1（NTR 1）。NTR 1通过作用于推定的NTR 1/多巴胺受体来调节多巴胺信号传导。 受体D2（D2 R）复合物。肽或小分子NTR 1激动剂在哺乳动物模型中的功效 成瘾使它们非常受欢迎，但它们都有副作用。NTR 1，像其他GPCR一样， 通过G蛋白和β-抑制蛋白介导的途径。最近，我们开发并表征了一种 新型小分子NTR 1配体，以化合物SBI-553为代表，其激活β-抑制蛋白， 刺激G蛋白信号传导。这种类型的功能选择性/偏置信号处理提供了一个机会， 产生更直接的生理作用并减少不想要的副作用。我的初步发现很有希望 这表明SBI-553减弱了没有低血压的小鼠中阿片样物质和兴奋剂相关的行为， 无偏NTR 1激动作用的低温特征。本申请的目的是阐明本发明的实施例。 β-抑制蛋白偏向NTR 1配体减弱药物相关行为的机制，并验证其 通过整合小鼠自身给药和功能性神经成像来提高治疗潜力。我的中枢 假设NTR 1处的选择性β-抑制蛋白激活减弱成瘾样行为和相关的 通过拮抗D2 R功能改变局部脑代谢。这一假设将由以下人员进行检验： 追求三个具体目标，使用SBI-553作为工具化合物。我将首先（1）K99）定义行为效应 通过在基因工程小鼠中进行自我给药研究，我会 然后（2）K99）使用最先进的小分子生物学方法确定β-抑制蛋白偏向NTR 1配体的生理作用。 动物正电子发射断层扫描/计算机断层扫描（PET/CT）。最后，我将利用我的新训练， 小鼠自身给药和PET/CT，以独立（3）R 00）评价D2 R对效应的贡献 β-arrestin偏向NTR 1配体。追求这些目标需要动物模型的跨学科培训 成瘾和神经影像学来补充我之前的分子生物学研究。所以我 召集专家合作者组成跨学科指导委员会，由Marc Caron博士担任主席 （导师）和劳伦斯巴拉克（共同导师）。位于杜克大学的卡隆实验室 来回答关于GPCR信号偏差的问题我们制定了个性化的培训计划 这将为我提供管理一个多产的独立实验室所需的科学和专业技能， 并将成瘾作为一种脑部疾病进行研究，包括其神经学病因和行为表现。

Abstract: Opioid and psychostimulant addictions are large and growing public health concerns that are inadequately managed with available therapeutics. The objective of this proposal directly addresses this unmet clinical need, as it includes the evaluation of a novel anti-addiction therapeutic strategy. A shared feature of addictive drugs is their ability to induce inappropriate activation of the mesolimbic dopamine system. Restoration of dopamine signaling homeostasis may be achieved by targeting the G protein-coupled receptor (GPCR) neurotensin receptor 1 (NTR1). NTR1 modulates dopamine signaling via action at putative NTR1/dopamine receptor D2 (D2R) complexes. The efficacy of peptide or small molecule NTR1 agonists in animal models of addiction have made them highly desirable but they all have side effects. NTR1, like other GPCRs, signals through both G protein- and β-arrestin-mediated pathways. Recently, we have developed and characterized a novel class of small molecule NTR1 ligands, typified by compound SBI-553, which activates β-arrestin without stimulating G protein signaling. This type of functional selectivity/biased siganling presents an opportunity to produce more directed physiological action and reduce unwanted side effects. My promising initial findings suggest that SBI-553 attenuates opioid and stimulant-associated behaviors in mice without the hypotension and hypothermia characteristic of unbiased NTR1 agonism. The objectives of this application are to elucidate the mechanism by which β-arrestin biased NTR1 ligands attenuate drug-associated behaviors and validate their therapeutic potential by integrating murine self-administration and functional neuroimaging. My central hypothesis is that selective β-arrestin activation at NTR1 attenuates addiction-like behaviors and associated changes in regional brain metabolism through antagonism of D2R function. This hypothesis will be tested by pursuing three specific aims, using SBI-553 as a tool compound. I will first (1) K99) define the behavioral effects of β-arrestin biased NTR1 ligands by conducting self-administration studies in genetically engineered mice. I will then (2) K99) determine the physiological effects of β-arrestin biased NTR1 ligands using state-of-the-art small animal positron emission tomography/computed tomography (PET/CT). Finally, I will use my new training in murine self-administration and PET/CT to independently (3) R00) evaluate the contribution of D2R to the effects of β-arrestin biased NTR1 ligands. Pursuit of these aims requires interdisciplinary training in animal models of addiction and neuroimaging to complement my previous studies in molecular biology. Therefore, I have assembled expert collaborators into an interdisciplinary mentoring committee, chaired by Drs. Marc Caron (Mentor) and Lawrence Barak (Co-Mentor). The Caron laboratory at Duke University is uniquely well-positioned to answer questions regarding biased GPCR signaling. We have developed an individualized training plan that will provide me with the scientific and professional skills required to run a productive, independent laboratory and study addiction as a brain disease, including its neurological etiology and behavioral manifestations.