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）：神经素（NT）是脑肽，可调节与精神病和抗精神病药的治疗作用有关的脑途径。融合证据表明，当前抗精神病药的治疗作用是通过刺激内源性NT介导的。基于这些证据，已经提出，针对NT系统可能是开发新型抗精神病药的生产策略。 NT1受体与NT的抗精神病药作用有关。最近开发的NT Mimetics在外围给药后进入大脑，有选择地靶向NT1受体，为研究这种可能性提供了出色的工具。主要研究者实验室的初步发现表明，这些NT1激动剂在动物模型中产生了高度稳健的抗精神病药物。在某些情况下，NT1激动剂的作用比现有抗精神病药所表现出的作用更强大。这些高度健壮的效果的基础机制尚不清楚。提出的研究有两个广泛的目标。首先要扩大有希望的证据，即NT1激动剂具有新型抗精神病药的潜力，特别是集中在令人兴奋的初步发现上，即它们可能对与精神分裂症相关的认知缺陷具有疗效，这是一个强烈需要更好治疗的领域。该目标将通过测试NT1激动剂在与精神分裂症相关的认知缺陷模型中的影响来实现。第二个目标是阐明内源性NT和外源性NT1激动剂的APD样作用的脑电路。具体而言，实验将检验以下假设：响应现有的抗精神病药而释放的外源给予的NT1激动剂和内源性NT通过激活位于抗精神病患者中现有抗精神病药作用的位点的NT1受体，从而产生抗精神病药样作用。该目标将通过多种实验技术实现，包括将选择性NT1拮抗剂施加到候选大脑部位，以阻止NT1激动剂和现有抗精神病药的影响，这些动物模型可以预测抗精神病药活性。如果得到证实，这将强烈支持NT1激动剂发展为潜在的“突破”抗精神病药的基本原理，这些抗精神病药可能相对于现有抗精神病药而具有优势，因为它们绕过了现有抗精神病药激活的抗精神病生途径的初始元素。这也将大大增加我们当前对现有抗精神病药作用机制的理解。公共卫生相关性：精神分裂症是一种使人衰弱的疾病，目前治疗不令人满意。我们提出的研究旨在研究开发靶向神经素的新型治疗方法，即神经素（一种天然化学物质）。提出的实验可能有助于导致精神分裂症的完全新颖和出色的治疗方法。