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

项目摘要-摘要 药物成瘾是一种潜在的心理健康问题，几乎没有有效的治疗方法。这 该提案是PI（Hnasko博士）和Sanford Burnham Prebys之间的合作努力 医学发现研究所（SBP）。SBP最近发现了ML 314和小分子 作为偏向性正变构剂作用于1型神经降压素受体（NtsR 1）的类似物 调节剂（PAM）。神经降压素（NT）激动剂长期以来一直被寻求作为潜在的治疗方法 对于药物成瘾或其他精神疾病，由于这种肽与 中脑多巴胺系统事实上，多巴胺神经元同时表达肽和 受体; NT已被证明是多巴胺信号传导的重要调节剂 跨多个系统。SBP开发的一种有前途的ML 314衍生物NtsR 1 PAM， 显示出优异的血脑屏障渗透性和ADME/Pk/Tox特性， 多个模型中的最小有效剂量为10 mg/kg。该化合物还显示， 有望使精神分裂症和成瘾的临床前模型的行为正常化。但 尽管在体外使用基于细胞的测定进行了大量的分子药理学表征， 以及上述有希望的药代动力学和行为数据， 了解SBP如何产生NtsR 1 PAM，影响生理完整性， 神经回路理解这一点对于指导这些有前途的药物走向 适当的临床应用，开发适当的临床疗效生物标志物，以及 开发出更精细的类似物。因为多巴胺是一个重要的参与者 许多形式的精神疾病，特别是吸毒成瘾;我们建议使用鼠标 模型和脑切片制备来表征NtsR 1 PAM对多巴胺 神经元兴奋性和多巴胺神经元释放特性， 电化学和光遗传学方法。我们还将评估NtsR 1 PAM如何调节 药物成瘾/依赖动物模型中的多巴胺神经元可塑性和行为。 因此，这些实验的直接目的是加速已经高度发达的 开发和非常有前途的配体向前走向精神疾病的临床治疗， 强调吸毒成瘾。

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.