Antipsychotics: Temporal Effects on Cognitive Function

抗精神病药：对认知功能的时间影响

• 批准号: 6704729
• 负责人: ALVIN V TERRY
• 金额: $ 26.08万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6704729
• 关键词: antipsychotic agents; autoradiography; behavior test; chlorpromazine; choline; clozapine; cognition; disease /disorder model; drug adverse effect; enzyme linked immunosorbent assay; growth factor receptors; haloperidol; immunofluorescence technique; in situ hybridization; laboratory rat; learning; memory; neurotransmitter metabolism; neurotrophic factors; receptor expression; risperidone; schizophrenia; western blottings

DESCRIPTION (provided by applicant): Schizophrenia is a debilitating illness that affects up to 1% of the world's population. While the use of antipsychotic (neuroleptic) drugs is the standard of care for treating the psychotic symptoms of the illness, little is known regarding which neuroleptics are best for extended use in those with cognitive impairment. This consistent feature of schizophrenia is now believed to have the most substantial impact on the longterm outcome of the disease. Accordingly, a major long-term goal of this laboratory is to develop mechanistically-based therapeutic strategies for patients suffering from psychotic symptoms and cognitive dysfunction. The objective of this application is to establish potential relationships between the cellular and biochemical effects of chronic neuroleptic exposure and cognitive function in an experimental animal model. We have compelling preliminary evidence from rat studies that chronic exposure to conventional neuroleptics such as haloperidol (in a temporally dependent fashion), but not atypical agents such as clozapine, leads to cognitive impairment and that a reduction in a key marker for cholinergic neurons, choline acetyltransferase, precedes the cognitive symptoms. Due to the pattern of reduced cholinergic enzyme staining and the fact that many of the cholinergic neurons involved in learning and memory are functionally dependent on the neurotrophin, nerve growth factor (NGF), we have developed the hypothesis that chronic exposure to conventional, but not atypical, neuroleptics in rats decreases neurotrophic support to cholinergic neurons, resulting in decreased cholinergic activity in the brain and impairment of cognitive function. The rationale for the proposed animal studies is that a better understanding of the differential (chronic) effects of neuroleptics on memory function will facilitate future (clinical) efforts to identify optimal drugs for cognitively impaired psychiatric patients. To test the hypothesis we propose two specific aims: 1): To evaluate differential temporal effects of different classes of neuroleptic drugs on cognitive function in an experimental animal model. 2): To define potential correlative relationships between neuroleptic-induced cognitive changes and temporal changes in biochemical and cellular parameters of cholinergic function in the brain, NGF release, and NGF receptor expression. We will use a water maze task to measure spatial learning, an 8-arm radial arm maze task to assess working memory, and in situ hybridization, western blots, ELISA experiments, immunofluorescence staining, and receptor autoradiography to measure the expression of NGF and key cholinergic markers. We expect that chronic exposure to conventional, but not atypical neuroleptics will negatively affect both spatial learning and working memory and that neuroleptic-induced alterations in CNS cholinergic activity will both precede and correlate with detectable manifestations of cognitive dysfunction. These studies, designed to mechanistically define neuroleptics based on their chronic effects on specific biological substrates of memory are significant because they will contribute to the identification of therapeutic agents with optimal effects on cognitive function, and thus potentially benefit many psychiatric patients.

描述（由申请人提供）：精神分裂症是一种使人衰弱的疾病，影响着世界上多达 1% 的人口。虽然使用抗精神病药（精神安定药）是治疗该疾病的精神病症状的标准治疗方法，但对于哪些精神安定药最适合认知障碍患者的长期使用，人们知之甚少。现在认为精神分裂症的这一一致特征对该疾病的长期结果具有最重大的影响。因此，该实验室的一个主要长期目标是为患有精神病症状和认知功能障碍的患者开发基于机械的治疗策略。本申请的目的是在实验动物模型中建立慢性抗精神病药物暴露的细胞和生化效应与认知功能之间的潜在关系。 我们从大鼠研究中获得了令人信服的初步证据，表明长期接触氟哌啶醇等传统精神安定药（以时间依赖性方式），而不是氯氮平等非典型药物，会导致认知障碍，并且胆碱能神经元关键标志物胆碱的减少乙酰转移酶，先于认知症状。由于胆碱能酶染色减少的模式以及许多参与学习和记忆的胆碱能神经元在功能上依赖于神经营养蛋白、神经生长因子（NGF）这一事实，我们提出了这样的假设：长期暴露于传统的，但不是非典型的精神安定药会减少大鼠对胆碱能神经元的神经营养支持，导致大脑胆碱能活性降低和认知功能受损。拟议的动物研究的基本原理是，更好地了解精神安定药对记忆功能的差异（慢性）影响将有助于未来（临床）努力为认知障碍的精神病患者确定最佳药物。为了检验这一假设，我们提出了两个具体目标：1）：在实验动物模型中评估不同类别的精神安定药物对认知功能的差异时间影响。 2)：定义抗精神病药物引起的认知变化与大脑胆碱能功能的生化和细胞参数、NGF 释放和 NGF 受体表达的时间变化之间的潜在相关关系。我们将使用水迷宫任务来测量空间学习，使用 8 臂径向臂迷宫任务来评估工作记忆，并使用原位杂交、蛋白质印迹、ELISA 实验、免疫荧光染色和受体放射自显影来测量 NGF 和关键蛋白的表达。胆碱能标记物。我们预计，长期接触传统而非非典型的精神安定药会对空间学习和工作记忆产生负面影响，并且安定药引起的中枢神经系统胆碱能活动的改变将先于可检测到的认知功能障碍表现并与之相关。这些研究旨在根据精神安定药对记忆的特定生物底物的慢性影响来机械地定义精神安定药，其意义重大，因为它们将有助于识别对认知功能具有最佳效果的治疗药物，从而可能使许多精神病患者受益。