CHOLINERGIC TREATMENT OF SCHIZOPHRENIA

尼古丁激动剂治疗精神分裂症源于该中心对阿尔法7作用的发现 烟碱型乙酰胆碱受体及其基因CHRNA7在慢性阻塞性肺疾病病理生理和遗传传递中的作用 有患精神分裂症的风险。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一种更安全、更有效的激动剂。3-2，4 由William Kem在核心C中首次合成的二甲氧基亚苄基苯甲醚(DMXB-A)可以是 口服给药，产生的快速反应比尼古丁少。它还具有更有利的安全性 侧写。该中心进行的1期和2期试验显示，在神经认知方面有良好的效果 精神分裂症患者。然而，这一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在神经认知和治疗中发挥最大作用的能力 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 可以获得。 使用功能磁共振成像对神经生物学效应的成像显示，DMXB-A减少了 海马体，一个与精神分裂有关的特征，并增加内侧隔核的活动， 海马胆碱能神经支配的来源，包括抑制作用的α7烟碱受体 中间神经元。这一成像策略将用于确定更长作用的DMXB-A是否增加 神经生物学效应或其效应是否受到快速反应的限制。 我们的研究已经在非吸烟者身上进行，以避免可能的脱敏干扰 精神分裂症患者长期大量滥用尼古丁对尼古丁的影响。随着新的持续释放 准备好后，我们可以测试DMXB-A是否会在戒烟的情况下取代尼古丁 治疗方案。我们将使用功能磁共振成像来帮助评估尼古丁对DMXB-A的干扰程度 正在尝试戒烟的精神分裂症患者使用DMXB-A治疗的效果。 项目1从项目3、4、5和6获得基础研究支持。核心C提供DMXB-A。 相关性(请参阅说明)： 精神分裂症需要新的治疗策略来改善认知功能障碍和负性 并能预防精神病的发展。该中心研究一种烟碱型乙酰胆碱 受体作为新的治疗靶点。研究结果被用来设计一种新的药物治疗方法 精神分裂症和婴儿发育期间的预防性营养干预，两者都激活了这一 R(ARP&>ntnr

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