CHOLINERGIC TREATMENT OF SCHIZOPHRENIA

精神分裂症的胆碱能治疗

• 批准号: 8515782
• 负责人: ROBERT R FREEDMAN
• 金额: $ 1.71万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515782
• 关键词: Agonist; Animal Model; Antipsychotic Agents; Basic Science; Brain; Chronic; Clinical; Clinical Trials; Cognitive; Data; Development; Dopamine; Effectiveness of Interventions; Functional Magnetic Resonance Imaging; Functional disorder; Genes; Genetic; Glutamates; Grant; Half-Life; Hippocampus (Brain); Image; Impaired cognition; Infant Development; Instruction; Interneurons; Intervention; Intervention Trial; Learning; Medial Septal Nucleus; Molecular; Molecular Genetics; Molecular Neurobiology; Muscarinic Agonists; National Institute of Mental Health; Neurobiology; Neurocognition; Neurocognitive; Nicotine; Nicotinic Agonists; Nicotinic Receptors; Nutrient; Patients; Persons; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Property; Psychotic Disorders; Reporting; Research Support; Resources; Risk; Role; Safety; Schizophrenia; Smoking; Source; Sustained-Release Preparation; Symptoms; Tachyphylaxis; Testing; Therapeutic Effect; Translational Research; Withholding Treatment; anabaseine; base; cholinergic; clinical effect; design; improved; innovation; nerve supply; new therapeutic target; nicotine abuse; non-smoker; novel therapeutics; prevent; sensory gating; smoking cessation; therapeutic target; trait; transmission process; treatment program

Nicotinic agonist therapy for schizophrenia arose from the Center's discovery of the role of the alpha 7 nicotinic acetylcholine receptor and its gene CHRNA7 in the pathophysiology and genetic transmission of risk for schizophrenia. Although nicotine itself has many undesirable properties, its effects on neurocognition and sensory gating in schizophrenia prompted the search for a safer, more effective agonist. 3-2,4 dimethoxybenzylidene anabaseine (DMXB-A), first synthesized by William Kem in Core C, can be administered orally and produces less tachyphylaxis than nicotine. It also has a more favorable safety profile. Phase 1 and Phase 2 trials conducted by the Center showed promising effects on neurocognition in patients with schizophrenia. Nevertheless, the full possibilites of this target have not yet been determined. DMXB-A's relatively short half life may limit its ability to achieve maximal effects on neurocognition and clinical symptoms. Therefore, we will test a sustained release preparation to assess if more robust effects can be obtained. Imaging of the neurobiological effects using fMRI shows that DMXB-A diminishes hyperactivation of the hippocampus, a trait associated with schizophenia, and increases activity in the medial septal nucleus, the source of cholinergic innervation to the hippocampus, including the alpha 7 nicotinic receptors on inhibitiory interneurons. This imaging strategy will be used to determine if longer acting DMXB-A has increased neurobiological effects or whether its effects are limited by tachyphylaxis. Our studies have been performed in non-smokers to avoid interference from the possible desensitizing effects of nicotine from schizophrenics' heavy chronic nicotine abuse. With the new sustained release preparation, we can test whether DMXB-A will substitute for nicotine in the contextof a smoking cessation treatment program. We will use fMRI to help assess the degree to which nicotine interferes with DMXB-A's effects as persons with schizophrenia who are trying to stop smoking are treated with DMXB-A. Project 1 receives basic research support from Projects 3, 4, 5, and 6. Core C provides DMXB-A. RELEVANCE (See instructions): New therapeutic strategies for schizophrenia are needed to improve cognitive dysfunction and negative symptoms and to prevent the development of psychosis. The Center investigates a nicotinic acetylcholine receptor as a new therapeutic target. Investigational results are used to design a new drug treatment for schizophrenia and a preventative nutrient intervention during infant development, both of which activate this r(arp>ntnr

治疗精神分裂症的烟碱激动剂疗法源于该中心发现 α7 的作用 烟碱乙酰胆碱受体及其基因CHRNA7在病理生理学和遗传传递中的作用 精神分裂症的风险。尽管尼古丁本身有许多不良特性，但它对神经认知的影响 精神分裂症的感觉门控促使人们寻找更安全、更有效的激动剂。 3-2,4 二甲氧基亚苄基阿那巴碱 (DMXB-A)，首先由 William Kem 在 Core C 中合成，可以 口服给药，产生的快速耐受性比尼古丁少。它还具有更有利的安全性 轮廓。该中心进行的第一阶段和第二阶段试验显示出对神经认知的有希望的影响 精神分裂症患者。然而，该目标的全部可能性尚未确定。 DMXB-A 相对较短的半衰期可能会限制其对神经认知和神经功能实现最大影响的能力。 临床症状。因此，我们将测试缓释制剂，以评估是否有更强劲的效果 可以得到。 使用 fMRI 对神经生物学效应进行成像表明，DMXB-A 可以减少神经元的过度激活 海马体，一种与精神分裂症相关的特征，并增加内侧间隔核的活动， 海马胆碱能神经支配的来源，包括抑制性的 α7 烟碱受体 中间神经元。该成像策略将用于确定长效 DMXB-A 是否增加 神经生物学作用或其作用是否受到快速耐受的限制。 我们的研究是在非吸烟者中进行的，以避免可能的脱敏作用的干扰 精神分裂症患者长期严重滥用尼古丁对尼古丁的影响。随着新的持续发布 准备工作中，我们可以测试DMXB-A是否可以在戒烟的情况下替代尼古丁 治疗方案。我们将使用 fMRI 来帮助评估尼古丁干扰 DMXB-A 的程度 尝试戒烟的精神分裂症患者接受 DMXB-A 治疗时的效果。 项目1得到项目3、4、5和6的基础研究支持。核心C提供DMXB-A。 相关性（参见说明）： 精神分裂症需要新的治疗策略来改善认知功能障碍和消极情绪 症状并防止精神病的发展。该中心研究烟碱乙酰胆碱 受体作为新的治疗靶点。研究结果用于设计新的药物治疗方法 精神分裂症和婴儿发育期间的预防性营养干预，两者都会激活这种 r（arp>ntnr）