Neurophysiological Characterization of Novel Neurotensin Receptor Ligands to Define Therapeutic Potential in Combatting Addiction

项目摘要-摘要 毒瘾是一种潜伏的心理健康问题，几乎没有有效的治疗方法。这 提案是PI(Hnasko博士)和Sanford Burnham Prebys共同努力的结果 医学发现研究所(SBP)。SBP最近发现了ML314和小分子 作用于神经降压素受体1型(NtsR1)的类似物作为偏向正别构 调制器(PAM)。长期以来，神经降压素(NT)激动剂一直被寻求作为潜在的治疗方法 用于药物成瘾或其他精神疾病，这是由于该肽与 中脑多巴胺系统。事实上，多巴胺神经元既表达多肽，又表达 受体；NT已被证明是多巴胺信号的重要调节器 跨多个系统。SBP开发了一种有前途的ML314衍生物NtsR1 PAM。 显示出出色的血脑屏障穿透性和ADME/PK/Tox特性，支持 最小有效剂量在10毫克/公斤的多个型号中。这种化合物也显示出 承诺在精神分裂症和成瘾的临床前模型中使行为正常化。但 尽管在体外使用基于细胞的分析进行了大量的分子药理学表征， 上面描述的有希望的药代动力学和行为数据，很少是 了解SBP开发的NtsR1 PAM如何影响生理完整 神经回路。了解这一点对于将这些有希望的药物引向 适当的临床应用/S，开发适当的临床疗效生物标志物，以及 开发进一步精炼的类似物。因为多巴胺是这些表现中的中心角色 多种形式的精神疾病，特别是毒瘾；我们建议使用老鼠 研究NtsR1PAMs对多巴胺影响的模型和脑片制备 使用电生理学的神经元兴奋性和多巴胺神经元释放特性 电化学法和光遗传学方法。我们还将评估NtsR1 PAM如何调节 药物成瘾/依赖动物模型中多巴胺神经元的可塑性和行为。 因此，这些实验的目的是直接加速本已高度发达的 开发出非常有前途的配体，用于精神疾病的临床治疗，具有 对吸毒成瘾的重视。

PROJECT SUMMARY – ABSTRACT Drug addiction is an insidious mental health problem that has few effective therapies. This proposal is a collaborative effort between the PI (Dr. Hnasko) and the Sanford Burnham Prebys Medical Discovery Institute (SBP). SBP has recently identified ML314 and small molecule analogs that act at the Neurotensin receptor type 1 (NtsR1) as biased positive allosteric modulators (PAM). Neurotensin (NT) agonists have long been sought as potential treatments for drug addiction or other psychiatric illness due to the close association of this peptide with the midbrain dopamine system. Indeed, dopamine neurons express both the peptide and the receptor; and NT has been shown to act as an important modulator of dopamine signaling across multiple systems. A promising ML314 derivative NtsR1 PAM developed by SBP has shown excellent blood brain barrier penetration and ADME/Pk/Tox properties that support minimal efficacious doses across multiple models of 10 mg/kg. This compound has also shown promise in normalizing behaviors in pre-clinical models of schizophrenia and addiction. But despite substantial molecular pharmacology characterization using cell-based assays in vitro, and the promising pharmacokinetic and behavioral data described above, very little is understood about how the NtsR1 PAMs developed by SBP influence physiologically intact neural circuits. Understanding this is crucial for directing these promising drugs toward appropriate clinical application/s, developing appropriate biomarkers of clinical efficacy, and developing further refined analogs. Because dopamine is a central player in the manifestations of numerous forms of mental illness, particularly drug addiction; we propose to use mouse models and brain slice preparations to characterize the effects of NtsR1 PAMs on dopamine neuron excitability and dopamine neuron release properties using electrophysiological, electrochemical, and optogenetic approaches. We will also assess how NtsR1 PAMs modulate dopamine neuron plasticity and behavior in animal models of drug addiction/dependence. These experiments are thus aimed directly at accelerating the path of an already highly developed and very promising ligand forward toward the clinical treatment of mental illness, with an emphasis on drug addiction.