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）通常用于临床管理这些行为后遗症，尽管缺乏对后续恢复的影响的研究。我们实验室的研究表明，短期和持续的暴露模式（即，每天一次给药19天）的APD氟哌啶醇（HAL）和利培酮（RISP）对大鼠TBI后的运动和认知功能产生负面影响。这些有害作用可能部分由D2受体拮抗作用介导，因为使用D2受体激动剂溴隐亭的平行实验证明了增强的功能恢复。因此，我们建议使用对D2受体具有不同药理学作用的临床相关APD来经验性地评估TBI后的功能恢复;具体而言，HAL（强D2拮抗剂），RISP（中等D2拮抗剂）和阿立哌唑（ARIP）是D2和5-HT 1A受体的部分激动剂。总之，我们假设ARIP（1）不会对功能恢复有害（因为缺乏D2受体拮抗剂效应），（2）会促进恢复（由于D2和/或5-HT 1A激动剂活性）。提出了三个具体的目标来检验总体假设。目标1将比较短期（3周）和长期（3个月和6个月）ARIP短期和持续暴露于HAL和RISP对运动的影响（平衡木/行走和旋转杆），认知（空间学习/记忆保持），组织学（CA 1/CA 3细胞存活率，皮质病变体积），蛋白质印迹（D2/5-HT 1A受体表达）和TBARS（氧化应激）结果。目标2将比较间歇给药的短期和长期效果（即，每2、3、4或5天一次）在与目标1相同的终点上进行HAL、RISP和ARIP。间歇给药的基本原理是，在临床康复期间，并非所有激越患者都需要每日APD干预，因此接受prn（即，根据需要）或间歇剂量。目标3将评估调节效应 康复相关的环境富集（EE）的运动，认知，组织学和氧化作用的HAL，RISP和ARIP的范例，检查短期和一致的暴露和间歇性给药。EE范式模仿康复环境的认知、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真实的世界康复实践。此外，这些目标将使我们了解APD介导有害（例如，HAL和RISP）或潜在有益的（例如，ARIP）在TBI后的作用，并且可能有助于发现试剂以（1）对抗TBI诱导的激动和攻击而不负面影响行为恢复，以及（2）通过增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TBI后APD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.