DBS and Rodent Antidepressant- Screen Models

DBS 和啮齿动物抗抑郁药 - 筛选模型

• 批准号: 7454336
• 负责人: Ziad Nahas
• 金额: $ 17.65万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-05 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7454336
• 关键词: Acids; Acute; Adverse effects; Affective; Agonist; Amygdaloid structure; Animal Experimentation; Animal Model; Anterior; Antidepressive Agents; Area; Award; Baclofen; Behavioral; Bilateral; Brain; Brain Stem; Cell Nucleus; Classification; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Complement; Condition; Coupled; Daily; Deep Brain Stimulation; Depressed mood; Development; Discipline; Dorsal; Double-Blind Method; Economics; Educational process of instructing; Electroconvulsive Therapy; Electrodes; Enkephalins; FOS gene; Fluoxetine; Fostering; Functional disorder; Future; Gene Expression; Human; Implant; Injection of therapeutic agent; Intraperitoneal Injections; Invasive; K-Series Research Career Programs; Knowledge; Link; Measures; Medial; Medical; Mental Depression; Mentored Clinical Scientist Development Award (K08); Mentors; Methods; Modeling; Mood Disorders; Muscimol; National Institute of Mental Health; Neurons; Outcome Measure; Parkinson Disease; Patients; Pharmaceutical Preparations; Play; Population; Positioning Attribute; Prefrontal Cortex; Psychiatrist; Rattus; Recommendation; Recruitment Activity; Research; Research Methodology; Research Personnel; Resistance; Rodent; Role; Saline; Scientist; Site; Skiing; Sprague-Dawley Rats; Staining method; Stains; Strategic Planning; Stress; Swimming; System; Techniques; Testing; Therapeutic; Time; Training; Translational Research; Translations; Work; aging brain; base; cingulate cortex; depressive symptoms; design; dorsal raphe nucleus; immunocytochemistry; man; monoamine; neuropsychiatry; receptor; response; skills; treatment delivery technique

DESCRIPTION (provided by applicant): Depression is a prevalent neuropsychiatric illness with devastating medical and socio-economic consequences. Although many patients respond to current treatments, up to 25% do not respond, or have substantial side effects. New treatments are desperately needed. This application for Mentored Clinical Scientist Development Award responds to the NIMH Strategic Plan for Mood Disorder Research recommendation to develop experts in translational research. Animal models of depression like the Forced Swim Test (FST) predict human antidepressant activity. Almost all antidepressant drugs and electro-convulsive therapy used in daily clinical practice have been validated with the FST. Deep brain stimulation (DBS) is an invasive technique that could potentially play a role in targeted antidepressant treatment delivery in medication resistant patients. DBS is postulated to inhibit dysfunctional brain systems implicated in maladaptive responses to stress and linked to the pathophysiology of depression. At the moment, enthusiasm for applying DBS in depressed populations is limited by the ethical concern that since these dysfunctional depression networks are not fully worked out in humans, it is unclear where to implant a DBS electrode in man. That is, there is inadequate basic animal research at the moment to support the choice of a targeted area. This proposal is designed to fill several of these gaps. It offers to train the candidate to become an expert in translation depression research, with training in DBS, predictors of antidepressant response in rodents, immunocytochemistry of immediate early gene expression and advanced research methodology. The scientific study within this training award is designed to teach the candidate new methods and approaches, while also answering important questions in this area. Sprague-Dawley rats will be divided into 12 groups in a parallel double-blind design and implanted with bilateral DBS to either the centro-medial amygdala (CMA), dorsal raphe (DR), or anterior cingulate cortex (ACC). Each group will receive an intraperitoneal injection of fluoxetine (FLX) (an effective antidepressant drug) or saline (SAL) and be stimulated with either active DBS (DBS) or sham DBS (NoSTM). Rats will be tested once (FLX/DBS, FLX/NoSTM, SAL/DBS, SAL/NoSTM). FST immobility time will serve as a primary outcome measure. 30 minutes from FST start, the brains will be stained for c-fos using immunocychemistry method. C-fos profiles will serve as exploratory measures of antidepressant response and regional circuitry. This K08 expands on and complements the candidate's special expertise in clinical research of electrical neuromodulation applied to mood disorders. The knowledge from this 5-year career development award will position him to better guide future therapeutic applications of DBS. Future work will bridge between validating these findings in more comprehensive models of depression and clinical investigations of the DBS antidepressant effect in patients with treatment resistant depression.

描述（由申请人提供）：抑郁症是一种普遍存在的神经精神疾病，具有毁灭性的医疗和社会经济后果。尽管许多患者对当前的治疗有反应，但高达 25% 的患者没有反应，或者有严重的副作用。迫切需要新的治疗方法。此次申请指导临床科学家发展奖是响应 NIMH 心境障碍研究战略计划关于培养转化研究专家的建议。强迫游泳测试（FST）等抑郁症动物模型可以预测人类的抗抑郁活性。日常临床实践中使用的几乎所有抗抑郁药物和电惊厥疗法都经过 FST 验证。深部脑刺激（DBS）是一种侵入性技术，可能在药物耐药患者的靶向抗抑郁治疗中发挥作用。 DBS 被认为可以抑制功能失调的大脑系统，该系统与压力适应不良反应有关，并与抑郁症的病理生理学有关。目前，在抑郁症人群中应用 DBS 的热情受到伦理问题的限制，因为这些功能失调的抑郁症网络在人类中尚未完全解决，因此尚不清楚在人类的何处植入 DBS 电极。也就是说，目前没有足够的基础动物研究来支持目标区域的选择。该提案旨在填补其中几个空白。它通过 DBS、啮齿动物抗抑郁反应预测因子、早期基因表达的免疫细胞化学和先进研究方法的培训，培训候选人成为转化抑郁症研究的专家。该培训奖项中的科学研究旨在向候选人传授新的方法和途径，同时回答该领域的重要问题。 Sprague-Dawley 大鼠将采用平行双盲设计分为 12 组，并在中央内侧杏仁核 (CMA)、中缝背侧 (DR) 或前扣带皮层 (ACC) 植入双侧 DBS。每组将接受腹腔注射氟西汀 (FLX)（一种有效的抗抑郁药物）或生理盐水 (SAL)，并用活性 DBS (DBS) 或假 DBS (NoSTM) 进行刺激。大鼠将被测试一次（FLX/DBS、FLX/NoSTM、SAL/DBS、SAL/NoSTM）。 FST 不动时间将作为主要结果指标。 FST 开始 30 分钟后，将使用免疫细胞化学方法对大脑进行 c-fos 染色。 C-fos 谱将作为抗抑郁反应和区域回路的探索性测量。 K08 扩展并补充了候选人在应用于情绪障碍的电神经调节临床研究方面的特殊专业知识。这个为期 5 年的职业发展奖所获得的知识将使他能够更好地指导未来 DBS 的治疗应用。未来的工作将在更全面的抑郁症模型中验证这些发现与 DBS 对难治性抑郁症患者的抗抑郁作用的临床研究之间建立桥梁。

项目成果

Anti-ceramidase LCL385 acutely reduces BCL-2 expression in the hippocampus but is not associated with an increase of learned helplessness in rats.

抗神经酰胺酶 LCL385 急剧降低海马中 BCL-2 的表达，但与大鼠习得性无助的增加无关。

• 发表时间: 2009-01-30
• 影响因子: 2.7
• 作者: Nahas, Ziad;Jiang, Yan;Zeidan, Youssef H;Bielawska, Alicja;Szulc, Zdzislaw;Devane, Lindsay;Kalivas, Peter;Hannun, Yusuf A
• 通讯作者: Hannun, Yusuf A

Relapse rates with long-term antidepressant drug therapy: a meta-analysis.

长期抗抑郁药物治疗的复发率：荟萃分析。

• 发表时间: 2009-07
• 作者: Williams, Nolan;Simpson, Annie N;Simpson, Kit;Nahas, Ziad
• 通讯作者: Nahas, Ziad

Inverse effects of oxytocin on attributing mental activity to others in depressed and healthy subjects: a double-blind placebo controlled FMRI study.

催产素对抑郁症和健康受试者将心理活动归因于他人的反向影响：一项双盲安慰剂对照 FMRI 研究。

• 发表时间: 2010
• 作者: Pincus D;Kose S;Arana A;Johnson K;Morgan PS;Borckardt J;Herbsman T;Hardaway F;George MS;Panksepp J;Nahas Z
• 通讯作者: Nahas Z