Understanding the Impact of Antipsychotic Drugs on Recovery After TBI

描述（由申请人提供）：在美国，每年大约有150万到200万人遭受创伤性脑损伤（TBI），其中许多人（24-96%）表现出躁动和攻击性。抗精神病药物（apd）通常用于临床管理这些行为后遗症，尽管缺乏对其对随后恢复的影响的研究。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，持续19天）的apd氟哌啶醇（HAL）和利培酮（RISP）对大鼠创伤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受体拮抗剂介导的，使用D2受体激动剂溴隐亭的平行实验表明，D2受体拮抗剂增强了功能恢复。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，对TBI后的功能恢复进行实证评估；具体来说，HAL（强D2拮抗剂），RISP（中度D2拮抗剂）和阿立哌唑（ARIP）是D2和5-HT1A受体的部分激动剂。总的来说，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)会增强恢复（由于D2和/或5-HT1A激动剂活性）。提出了三个具体目标来检验整个假设。目的1将比较短期和持续暴露于HAL和RISP的ARIP对运动（束平衡/行走和旋转），认知（空间学习/记忆保留），组织学（CA1/CA3细胞存活，皮质损伤体积），Western blot （D2/5-HT1A受体表达）和TBARS（氧化应激）结果的短期（3周）和长期（3和6个月）影响。Aim 2将比较HAL、RISP和ARIP间歇给药（即每2、3、4或5天一次）在与Aim 1相同终点上的短期和长期效果。间歇给药的理由是，在临床康复期间，并非所有躁动患者都需要每日APD干预，因此接受prn（即，根据需要）或间歇给药。目的3评估调节效应

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.