Neurotensin-1 Receptor as a Therapeutic Target for Schizophrenia

Neurotensin-1 受体作为精神分裂症的治疗靶点

基本信息

批准号：
8011722
负责人：
DAVID FEIFEL
金额：
$ 38.24万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-20 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8011722
关键词：
Abbreviations Accounting Affinity Agonist Amphetamines Animal Model Antipsychotic Agents Area Attenuated Blood - brain barrier anatomy Brain Bypass Cells Chemicals Clinical Clozapine Cognitive deficits Complement Development Disease Dopamine Down-Regulation Drug Delivery Systems Elements Exhibits Future Globus Pallidus Goals Haloperidol Health Knockout Mice Knowledge Laboratories Lead Medial Mediating Microdialysis Mus Neuraxis Neuropeptides Neurotensin Neurotensin Receptors Neurotransmitters Norway Nucleus Accumbens Pathway interactions Peptides Peripheral Pharmaceutical Resources Population Prefrontal Cortex Principal Investigator Process Psychotic Disorders Rattus Rattus norvegicus Relative (related person)Research Role Saline Schizophrenia Serotonin Short-Term Memory Site Social Discrimination System Techniques Testing Therapeutic Therapeutic Effect United States National Institutes of Health Visual attention Work base brain pathway design drug development drug efficacy gamma-Aminobutyric Acid genetic manipulation improved interest intraperitoneal mimetics neurochemistry neurotensin type 1 receptor novel overexpression postsynaptic pre-clinical predictive modeling prepulse inhibition processing speed receptor research study response social subcutaneous theories therapeutic target tool transmission process

项目摘要

DESCRIPTION (provided by applicant): Neurotensin (NT) is brain peptide that regulates brain pathways involved in psychosis and in the therapeutic effects of antipsychotic drugs. Converging evidence suggests that the therapeutic effects of current antipsychotic drugs are mediated by stimulation of endogenous NT. Based upon this evidence, it has been proposed that targeting the NT system may be a productive strategy for developing novel antipsychotic drugs. The NT1 receptor has been implicated in NT's antipsychotic effects. Recently developed NT mimetics that enter the brain after peripheral administration and selectively target NT1 receptors have provided excellent tools to investigate this possibility. Preliminary findings from the Principal Investigator's laboratory indicate that these NT1 agonists produce highly robust antipsychotic- like effects in animal models. In some cases the effects of the NT1 agonists are more robust than the effects exhibited by existing antipsychotic drugs. The mechanism underlying these highly robust effects is not known. The research proposed has two broad goals. First to expand on the promising evidence that that NT1 agonists have potential as novel antipsychotic drugs, focusing in particular on exciting preliminary findings that they may have efficacy on cognitive deficits associated with schizophrenia, an area strongly in need of better treatments. This goal will be accomplished by testing the effects of NT1 agonists in a battery of animal models of cognitive deficits that have relevance to schizophrenia. A second goal is to elucidate the brain circuitry underlying the APD-like effects of endogenous NT and exogenous NT1 agonists. Specifically, experiments will test the hypothesis that both exogenously administered NT1 agonists and endogenous NT released in response to existing antipsychotic drugs produce antipsychotic-like effects by activating NT1 receptors located downstream to the site of action of existing antipsychotic drugs in the antipsychosis pathway. This goal will be accomplished via a number of experimental techniques including administering selective NT1 antagonists into candidate brain sites in order to block the effects of an NT1 agonist and of existing antipsychotics in established animal models that are predictive of antipsychotic activity. If confirmed, this would strongly support the rationale for development of NT1 agonists as potential "breakthrough" antipsychotic drugs that could have advantages relative to existing antipsychotics because they bypass initial elements of the antipsychosis pathway activated by existing antipsychotic drugs. It would also significantly add to our current understanding of the mechanism by which existing antipsychotic drugs work. PUBLIC HEALTH RELEVANCE: Schizophrenia is a debilitating disorder for which current treatments are unsatisfactory. We propose studies aimed at investigating the possibility of developing novel treatments that target neurotensin, a natural chemical in the brain. The proposed experiments may help lead to completely novel and superior treatments for schizophrenia.

描述（由申请人提供）：神经降压素（NT）是调节与精神病和抗精神病药物的治疗作用有关的大脑通路的脑肽。综合证据表明，当前抗精神病药物的治疗效果是通过刺激内源性 NT 介导的。基于这一证据，有人提出，针对 NT 系统可能是开发新型抗精神病药物的有效策略。 NT1 受体与 NT 的抗精神病作用有关。最近开发的 NT 模拟物在外周给药后进入大脑并选择性地靶向 NT1 受体，为研究这种可能性提供了极好的工具。首席研究员实验室的初步研究结果表明，这些 NT1 激动剂在动物模型中产生高度强大的抗精神病样作用。在某些情况下，NT1 激动剂的作用比现有抗精神病药物所表现出的作用更强。这些高度稳健的效应背后的机制尚不清楚。拟议的研究有两个广泛的目标。首先扩展 NT1 激动剂有潜力作为新型抗精神病药物的有希望的证据，特别关注令人兴奋的初步发现，即它们可能对与精神分裂症相关的认知缺陷有效，而精神分裂症是一个迫切需要更好治疗的领域。这一目标将通过在一系列与精神分裂症相关的认知缺陷动物模型中测试 NT1 激动剂的效果来实现。第二个目标是阐明内源性 NT 和外源性 NT1 激动剂的 APD 样作用背后的大脑回路。具体来说，实验将检验以下假设：外源性施用的 NT1 激动剂和响应现有抗精神病药物而释放的内源性 NT 通过激活位于抗精神病途径中现有抗精神病药物作用位点下游的 NT1 受体而产生抗精神病样作用。这一目标将通过许多实验技术来实现，包括将选择性 NT1 拮抗剂施用到候选大脑部位，以阻断 NT1 激动剂和现有抗精神病药物在可预测抗精神病活性的已建立动物模型中的作用。如果得到证实，这将有力地支持开发 NT1 激动剂作为潜在“突破性”抗精神病药物的理由，该药物相对于现有抗精神病药物可能具有优势，因为它们绕过了现有抗精神病药物激活的抗精神病途径的初始元件。它还将极大地增进我们目前对现有抗精神病药物作用机制的理解。公共卫生相关性：精神分裂症是一种使人衰弱的疾病，目前的治疗效果并不令人满意。我们提出的研究旨在调查开发针对神经降压素（大脑中的一种天然化学物质）的新型治疗方法的可能性。所提出的实验可能有助于开发出全新且优越的精神分裂症治疗方法。