PHYSICAL ACTIVITY, ANTIDEPRESSENTS AND BDNF INDUCTION

体力活动、抗抑郁药和 BDNF 诱导

• 批准号: 2834218
• 负责人: AMELIA A RUSSO-NEUSTADT
• 金额: $ 1.56万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2834218
• 关键词: Alzheimer's disease; aggression; aging; animal old age; antidepressants; behavioral /social science research tag; clinical depression; comorbidity; drug screening /evaluation; electrophoresis; exercise; hippocampus; immunocytochemistry; in situ hybridization; laboratory rat; mature animal; mental disorder chemotherapy; messenger RNA; neuroprotectants; neurotransmitter metabolism; neurotrophic factors; nonhuman therapy evaluation; norepinephrine; nucleic acid probes; serotonin

DESCRIPTION: (Applicant's Abstract): Psychiatric/emotional disturbances such as aggression and depression affect a significant proportion of patients with Alzheimer's disease (AD). There is evidence outlined in this proposal that abnormalities in the serotonergic and noradrenergic neurotransmitter systems underlie these behavioral derangements; and that a shared common endpoint for the therapeutic effects of antidepressant compounds and other interventions for the treatment of these patients could be the regulation of brainderived neurotrophic factor (BDNF). Antidepressant medications, commonly prescribed treatments of choice for aggression/agitation and depression, have been shown to up-regulate BDNF mRNA in the hippocampus of chronically treated rats. A number of clinical studies have suggested that physical exercise significantly improves emotional status as well as cognitive function in elderly patients. This simple behavior, physical exercise, has been shown, in our own Institute, to lead to rapid BDNF mRNA induction in the rat brain. We hypothesize that BDNF regulation is a common result of each of these interventions, and that the responses to physical activity and antidepressant treatment are synergistic. Our preliminary results, outlined in this proposal, indicate that a combination of antidepressant drug treatment and general physical activity potentiates the level of BDNF mRNA within the adult rat hippocampus in an additive manner. We wish to further characterize this combined effect, and to determine its time course and dose-reponse in the aging brain. Following this characterization, we wish to test the hypothesis that the BDNF induction brought about by antidepressant treatment, physical activity or the combination takes place through noradrenergic and/or serotonergic systems, and to determine which of these is most vital to maintain the observed effect. We also wish to test the hypothesis that synaptic protein changes downstream of BNDF induction result from these interventions. The proposed experiments will provide information about the mechanism of drug treatments for depression and aggression; leading to the development of better, more specific interventions for emotional dyscontrol in AD and other neurodegenerative disorders of the elderly. It is proposed that emotional management in dementia can be improved by physical activity in conjunction with antidepressant agents.

描述：（申请人的摘要）：攻击性和抑郁等精神/情绪障碍影响很大一部分阿尔茨海默病（AD）患者。该提案中概述的证据表明，血清素能和去甲肾上腺素能神经递质系统的异常是这些行为紊乱的根源；抗抑郁化合物和其他治疗这些患者的干预措施的治疗效果的共同终点可能是脑源性神经营养因子（BDNF）的调节。抗抑郁药物是治疗攻击性/躁动和抑郁症的常用处方药物，已被证明可以上调长期治疗大鼠海马体中的 BDNF mRNA。多项临床研究表明，体育锻炼可显着改善老年患者的情绪状态和认知功能。我们自己的研究所已证明，这种简单的行为（体育锻炼）可导致大鼠大脑中 BDNF mRNA 的快速诱导。我们假设 BDNF 调节是这些干预措施的共同结果，并且对身体活动和抗抑郁治疗的反应是协同的。我们在本提案中概述的初步结果表明，抗抑郁药物治疗和一般体力活动的结合可以以相加的方式增强成年大鼠海马内 BDNF mRNA 的水平。我们希望进一步表征这种综合效应，并确定其在衰老大脑中的时间进程和剂量反应。根据这一特征，我们希望检验以下假设：抗抑郁治疗、体力活动或组合所引起的 BDNF 诱导是通过去甲肾上腺素能和/或血清素能系统发生的，并确定其中哪一个对于维持观察到的效果最重要。我们还希望检验以下假设：BNDF 诱导下游的突触蛋白变化是由这些干预措施造成的。拟议的实验将提供有关抑郁症和攻击性药物治疗机制的信息；从而开发出更好、更具体的干预措施来治疗 AD 和其他老年人神经退行性疾病的情绪失控。有人提出，通过体育活动与抗抑郁药物相结合，可以改善痴呆症的情绪管理。