Understanding the Impact of Antipsychotic Drugs on Recovery After TBI

了解抗精神病药物对 TBI 后恢复的影响

• 批准号: 8295688
• 负责人: ANTHONY E. KLINE
• 金额: $ 30.89万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8295688
• 关键词: 8-Hydroxy-2-(di-n-propylamino)tetralin; Address; Aggressive behavior; Agitation; Agonist; Animal Model; Antipsychotic Agents; Behavioral; Biological Assay; Bromocriptine; Cell Survival; Clinic; Clinical; Cognitive; Data; Dopamine D2 Receptor; Dose; Drug usage; Equilibrium; Exhibits; Figs - dietary; Haloperidol; Individual; Injury; Intervention; Knowledge; Laboratories; Learning; Lesion; Long-Term Effects; Malondialdehyde; Mediating; Moderate Exercise; Motor; Outcome; Oxidative Stress; Patients; Performance; Pharmacotherapy; Process; Rattus; Recovery; Recovery of Function; Regimen; Rehabilitation therapy; Research; Risk; Risperidone; Serotonin Receptor 5-HT1A; Social Environment; Testing; Therapeutic Effect; Thiobarbituric Acid Reactive Substances; Time; Traumatic Brain Injury; United States; Walking; Water; Western Blotting; aripiprazole; clinical care; clinical decision-making; clinically relevant; cognitive function; cognitive recovery; combat; controlled cortical impact; design; environmental enrichment for laboratory animals; improved; insight; memory retention; multidisciplinary; programs; receptor expression; research study

DESCRIPTION (provided by applicant): Approximately 1.5 to 2 million individuals suffer a traumatic brain injury (TBI) each year in the United States and many (24-96%) exhibit agitation and aggression. Antipsychotic drugs (APDs) are commonly used to clinically manage these behavioral sequelae despite a paucity of research into their effect on subsequent recovery. Studies from our laboratory have shown that a short and consistent exposure paradigm (i.e., once daily administration for 19 days) of the APDs haloperidol (HAL) and risperidone (RISP) negatively impact motor and cognitive function after TBI in rats. These detrimental effects may be mediated, in part, by D2 receptor antagonism as parallel experiments using the D2 receptor agonist, bromocriptine, demonstrated enhanced functional recovery. Hence, we propose to empirically evaluate functional recovery after TBI using clinically relevant APDs with different pharmacological actions on the D2 receptor; specifically, HAL (a strong D2 antagonist), RISP (a moderate D2 antagonist) and aripiprazole (ARIP) a partial agonist for the D2 and 5-HT1A receptors. Overall, we hypothesize that ARIP (1) will not be detrimental to functional recovery (because of a lack of D2 receptor antagonist effects), and (2) will enhance recovery (due to D2 and/or 5-HT1A agonist activity). Three specific aims are proposed to test the overall hypothesis. Aim 1 will compare both the short- term (3 weeks) and long-term (3 and 6 months) effects of short-and-consistent exposure of ARIP to HAL and RISP on motor (beam-balance/walk and rotarod), cognitive (spatial learning/memory retention), histological (CA1/CA3 cell survival, cortical lesion volume), Western blot (D2/5-HT1A receptor expression), and TBARS (oxidative stress) outcome after controlled cortical impact (CCI) injury. Aim 2 will compare both the short-term and long-term effects of intermittent dosing (i.e., once every 2, 3, 4, or 5 days) of HAL, RISP, and ARIP on the same endpoints as Aim 1. The rationale for intermittent dosing is that during clinical rehabilitation, not all patients with agitation require daily APD intervention and thus receive prn (i.e., as needed) or intermittent doses. Aim 3 will evaluate the moderating effect of a rehabilitation-relevant environmental enrichment (EE) paradigm on the motor, cognitive, and histological, and oxidative effects of HAL, RISP, and ARIP, examining both short and consistent exposure and intermittent dosing. The EE paradigm mimics the cognitive, physical, and social environment of rehabilitation settings. These various aims are designed to duplicate real world rehabilitation practice in an animal model. Additionally, these aims will inform our understanding of the mechanisms of APDs mediating the deleterious (e.g., HAL and RISP) or potentially beneficial (e.g., ARIP) effects after TBI and could possibly facilitate the discovery o agents to (1) combat TBI- induced agitation and aggression without negatively impacting behavioral recovery, and (2) positively impact outcome by enhancing the recovery process. Furthermore, these studies will have an immediate impact on clinical care by providing clinicians critical information about the effects of APDs after TBI. PUBLIC HEALTH RELEVANCE: To control agitation and aggression, which is exhibited in 24-96% of the 1.5 to 2 million individuals subjected to traumatic brain injury each year in the United States, antipsychotic drugs are commonly provided despite a paucity of research into their effect on the subsequent recovery process. Previous studies from our laboratory have shown that a short and consistent exposure paradigm (i.e., once daily administration for 19 days) of the antipsychotic drugs haloperidol and risperidone negatively impact motor and cognitive function after TBI in rats, which may be mediated, in part, by D2 receptor antagonism as parallel experiments using the D2 receptor agonist, bromocriptine, demonstrated enhanced functional recovery. Hence, we propose to evaluate motor and cognitive recovery after TBI by comparing haloperidol (a strong D2 antagonist), risperidone (a moderate D2 antagonist) and aripiprazole (a partial agonist for the D2 and 5-HT1A receptors) to test our overall hypothesis that aripiprazole (1) will not be detrimental to functional recovery (because of a lack of D2 receptor antagonist effects), and (2) will enhance recovery (due to D2 and/or 5-HT1A agonist activity), which will have an immediate impact by providing clinicians critical information about the effects of antipsychotic drugs after TBI.

描述（由申请人提供）：在美国，每年大约有 1.5 至 200 万人遭受创伤性脑损伤 (TBI)，其中许多人 (24-96%) 表现出烦躁和攻击性。抗精神病药物（APD）在临床上通常用于治疗这些行为后遗症，尽管对其对随后康复的影响的研究很少。我们实验室的研究表明，APD 氟哌啶醇 (HAL) 和利培酮 (RISP) 的短期持续暴露模式（即每天一次，持续 19 天）会对大鼠 TBI 后的运动和认知功能产生负面影响。这些有害影响可能部分是由 D2 受体拮抗作用介导的，因为使用 D2 受体激动剂溴隐亭的平行实验证明功能恢复增强。因此，我们建议使用对 D2 受体具有不同药理作用的临床相关 APD 来实证评估 TBI 后的功能恢复；具体来说，HAL（强效 D2 拮抗剂）、RISP（中度 D2 拮抗剂）和阿立哌唑 (ARIP)（D2 和 5-HT1A 受体的部分激动剂）。总体而言，我们假设 ARIP (1) 不会损害功能恢复（因为缺乏 D2 受体拮抗剂作用），并且 (2) 将增强恢复（由于 D2 和/或 5-HT1A 激动剂活性）。提出了三个具体目标来检验总体假设。目标 1 将比较 ARIP 短期持续暴露于 HAL 和 RISP 对运动（横梁平衡/行走和旋转）、认知（空间学习/记忆保留）、组织学（CA1/CA3 细胞存活、皮质病变体积）、蛋白质印迹（D2/5-HT1A 受体表达）和 TBARS（氧化）的短期（3 周）和长期（3 和 6 个月）影响 受控皮质冲击（CCI）损伤后的压力）结果。目标 2 将比较间歇给药（即每 2、3、4 或 5 天一次）HAL、RISP 和 ARIP 对与目标 1 相同的终点的短期和长期影响。间歇给药的基本原理是，在临床康复期间，并非所有躁动患者都需要每日 APD 干预，从而接受 prn（即根据需要）或间歇剂量。目标 3 将评估调节效应 康复相关的环境丰富 (EE) 范式对 HAL、RISP 和 ARIP 的运动、认知、组织学和氧化作用的影响，检查短期和一致的暴露以及间歇给药。 EE 范式模仿康复环境的认知、身体和社会环境。这些不同的目标旨在在动物模型中复制现实世界的康复实践。此外，这些目标将帮助我们了解 APD 介导 TBI 后有害（例如 HAL 和 RISP）或潜在有益（例如 ARIP）效应的机制，并可能有助于发现以下药物：（1）对抗 TBI 引起的躁动和攻击性，而不会对行为恢复产生负面影响；（2）通过增强恢复过程对结果产生积极影响。此外，这些研究将为临床医生提供有关 TBI 后 APD 影响的重要信息，从而对临床护理产生直接影响。 公共卫生相关性：控制激动和攻击行为，在美国每年有 1.5 至 200 万人遭受创伤性脑损伤，其中 24-96% 的人表现出这种情绪 各国普遍提供抗精神病药物，尽管对其对随后康复过程的影响的研究很少。我们实验室之前的研究表明，抗精神病药物氟哌啶醇和利培酮的短期持续暴露模式（即每天一次，持续 19 天）会对 TBI 后大鼠的运动和认知功能产生负面影响，这可能部分是通过 D2 受体拮抗作用介导的，因为使用 D2 受体激动剂溴隐亭的平行实验表明，功能恢复得到增强。因此，我们建议通过比较氟哌啶醇（强效 D2 拮抗剂）、利培酮（中度 D2 拮抗剂）和阿立哌唑（D2 和 5-HT1A 受体的部分激动剂）来评估 TBI 后的运动和认知恢复，以检验我们的总体假设，即阿立哌唑 (1) 不会损害功能恢复（因为缺乏 D2 受体） (2) 将促进恢复（由于 D2 和/或 5-HT1A 激动剂活性），这将为临床医生提供有关 TBI 后抗精神病药物作用的关键信息，从而产生立竿见影的效果。