Understanding the Impact of Antipsychotic Drugs on Recovery After TBI

描述(由申请人提供)：在美国，每年约有150万至200万人遭受创伤性脑损伤(TBI)，许多人(24%-96%)表现出激动和攻击性。抗精神病药物(APD)通常用于临床治疗这些行为后遗症，尽管对它们对后续康复的影响的研究很少。我们实验室的研究表明，短期和持续的APDS氟哌啶醇(HAL)和利培酮(RISP)暴露范例(即，每天一次，持续19天)对大鼠脑损伤后的运动和认知功能产生负面影响。使用D2受体激动剂溴隐亭的平行实验表明，功能恢复增强，这些有害影响可能部分通过D2受体拮抗作用而介导。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来经验性地评估脑损伤后的功能恢复；具体地说，HAL(强D2拮抗剂)、Risp(中等D2拮抗剂)和阿立哌唑(ARIP)是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)，以及(2)将促进恢复(由于D2和/或5-HT1A激动剂活性)。本文提出了三个具体的目标来检验整个假设。目的1比较ARIP短期(3周)和长期(3和6个月)对受控皮质撞击(CCI)损伤后运动(平衡木/行走和旋转棒)、认知(空间学习/记忆保持)、组织学(CA1/CA3细胞存活、皮质损伤体积)、Western印迹(D2/5-HT1A受体表达)和TBARS(氧化应激)结果的影响。目标2将在与目标1相同的终点上比较间歇给药(即每2、3、4或5天一次)HAL、RISP和ARIP的短期和长期效果。间歇给药的基本原理是，在临床康复期间，并不是所有有躁动的患者都需要每天的apd干预，从而接受Prn(即根据需要)或间歇剂量。目标3将评估缓和效果 对HAL、RISP和ARIP的运动、认知、组织学和氧化效应的康复相关环境浓缩(EE)范例进行研究，考察短期和持续暴露以及间歇剂量。EE范式模拟康复环境的认知、物理和社会环境。这些不同的目的是为了在动物模型中复制现实世界的康复实践。此外，这些目的将有助于我们理解APDS介导脑损伤后有害(如HAL和RISP)或潜在有益(如ARIP)效应的机制，并可能有助于发现(1)在不对行为恢复产生负面影响的情况下对抗脑损伤引起的激动和攻击，以及(2)通过加强恢复过程来积极影响结果。此外，这些研究将通过为临床医生提供有关颅脑损伤后APDS影响的关键信息，对临床护理产生直接影响。

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.