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

精神分裂症的尼古丁激动剂治疗源于该中心对α 7的作用的发现