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

新型神经降压素受体配体的神经生理学表征以确定对抗成瘾的治疗潜力

基本信息

批准号：
10427135
负责人：
Thomas Hnasko
金额：
--
依托单位：
VA SAN DIEGO HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10427135
关键词：
Acute Affect Affinity Agonist American Amino Acids Animal Model Antipsychotic Agents Arrestins Autoreceptors Behavior Behavioral Biological Availability Biological Markers Brain Brain region Cations Cells Characteristics Chronic Chronic Disease Clinical Treatment Clinical Trials Corpus striatum structure Coupled Data Dendrites Dependence Development Disease Dopamine Dose Drug Addiction Drug Kinetics Drug Modelings Electrophysiology (science)Extinction (Psychology)Family GTP-Binding Proteins Gene Expression Regulation Genes Glutamates Goals In Vitro Institutes Interruption Lead Ligands Measures Mediating Medical Mental Health Mental disorders Methods Midbrain structure Modeling Molecular Mus Neuropeptides Neurotensin Neurotensin Receptors Obesity Opioid Oral Peptide Receptor Peptides Periodicity Pharmaceutical Preparations Pharmacology Physiological Pre-Clinical Model Preparation Property Rewards Scanning Schizophrenia Signal Transduction Slice Speed Synapses System Testing Therapeutic Treatment Efficacy Veterans Viral Vector addiction analog base behavior influence blood-brain barrier penetration clinical application clinical efficacy conditioned place preference cost dopamine system dopaminergic neuron drug of abuse drug reward drug seeking behavior effective therapy experimental study gamma-Aminobutyric Acid in vitro Assay in vivo inward rectifier potassium channel maladaptive behavior mouse model neural circuit neurochemistry neuronal cell body neurophysiology neuroregulation neurotensin type 1 receptor novel opioid use optogenetics peptide analog positive allosteric modulator potential biomarker psychostimulant receptor internalization small molecule success

项目摘要

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.

项目摘要 - 摘要吸毒成瘾是一个阴险的心理健康问题，几乎没有有效的疗法。这提案是PI（Hnasko博士）和Sanford Burnham Prebys之间的合作努力医学发现研究所（SBP）。 SBP最近确定了ML314和小分子对神经素素受体1型（NTSR1）作用的类似物作为偏置阳性变构调节器（PAM）。神经素（NT）激动剂长期以来被视为潜在治疗由于这种胡椒与吸毒成瘾或其他精神疾病的关联中脑多巴胺系统。确实，多巴胺神经元表达胡椒和接收者; NT已被证明充当多巴胺信号的重要调节剂跨多个系统。 SBP开发的有希望的ML314衍生物NTSR1 PAM 显示出优质的血脑屏障渗透和支持的ADME/PK/TOX特性多种型号10 mg/kg的有效剂量最小。该化合物也显示了在精神分裂症和成瘾的临床前模型中的正常行为方面有望。但尽管在体外使用基于细胞的测定法进行了大量的分子药理学表征，但以及上述承诺的药代动力学和行为数据，几乎没有了解SBP开发的NTSR1 PAM如何影响生理上完好无损神经回路。了解这对于将这些有前途的药物引导到适当的临床应用，开发适当的临床效率生物标志物，以及开发进一步完善的类似物。因为多巴胺是表现形式的核心参与者多种形式的精神疾病，尤其是吸毒成瘾；我们建议使用鼠标模型和脑切片制剂以表征NTSR1 PAM对多巴胺的影响神经元激发和多巴胺神经元释放特性，使用电生理学，电化学和光遗传学方法。我们还将评估NTSR1 PAMS如何调节药物成瘾/依赖性动物模型中的多巴胺神经元可塑性和行为。因此，这些实验是直接旨在加速已经高度的路径开发和非常承诺的配体前进到精神疾病的临床治疗，强调吸毒成瘾。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Opponent control of behavioral reinforcement by inhibitory and excitatory projections from the ventral pallidum.

DOI：
10.1038/s41467-018-03125-y
发表时间：
2018-02-27
期刊：
Nature communications
影响因子：
16.6
作者：
Faget L;Zell V;Souter E;McPherson A;Ressler R;Gutierrez-Reed N;Yoo JH;Dulcis D;Hnasko TS
通讯作者：
Hnasko TS

Mechanism for differential recruitment of orbitostriatal transmission during actions and outcomes following chronic alcohol exposure.

DOI：
10.7554/elife.67065
发表时间：
2021-03-17
期刊：
eLife
影响因子：
7.7
作者：
Renteria R;Cazares C;Baltz ET;Schreiner DC;Yalcinbas EA;Steinkellner T;Hnasko TS;Gremel CM
通讯作者：
Gremel CM

VTA Glutamate Neuron Activity Drives Positive Reinforcement Absent Dopamine Co-release.

DOI：
10.1016/j.neuron.2020.06.011
发表时间：
2020-09-09
期刊：
Neuron
影响因子：
16.2
作者：
Zell V;Steinkellner T;Hollon NG;Warlow SM;Souter E;Faget L;Hunker AC;Jin X;Zweifel LS;Hnasko TS
通讯作者：
Hnasko TS