Antipsychotics: Temporal Effects on Cognitive Function

抗精神病药：对认知功能的时间影响

• 批准号: 6857149
• 负责人: ALVIN V TERRY
• 金额: $ 26.24万
• 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 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6857149
• 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）：精神分裂症是一种令人衰弱的疾病，影响了世界人口的1％。虽然使用抗精神病药（神经肌动蛋白）是治疗疾病精神病症状的护理标准，但对于哪些神经疗法最适合于认知障碍的人最适合扩展使用。现在据信，精神分裂症的这种一致特征对疾病的长期结果具有最大的影响。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制定基于机械的治疗策略。该应用的目的是在实验动物模型中建立慢性神经摄影暴露和认知功能的细胞和生化作用之间的潜在关系。 我们从大鼠研究中获得了令人信服的初步证据，即长期暴露于诸如氟哌啶醇（以时间依赖的方式），但不是氯氮平等非典型药物会导致认知障碍，并导致胆碱性神经元，胆碱性乙酰基酯酶的关键标记的降低。 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大脑中的胆碱能活性和认知功能的损害。拟议的动物研究的理由是，对神经动物对记忆功能的差异（慢性）影响有更好的了解将有助于未来（临床）努力，以确定认知障碍的精神病患者的最佳药物。为了检验假设，我们提出了两个具体目的：1）：评估不同类别的神经摄影药对实验动物模型中认知功能的差异时间影响。 2）：定义神经肌肉诱导的认知变化与胆碱能功能的生化和细胞参数的时间变化之间的潜在相关关系，NGF释放和NGF受体表达。我们将使用水迷宫任务来测量空间学习，8臂径向手臂迷宫的任务来评估工作记忆，以及原位杂交，蛋白质印迹，ELISA实验，免疫荧光染色以及受体自身自我自我自我自我摄影，以测量NGF表达和关键的胆碱能标记。我们预计长期暴露于常规但非典型神经疗法会对空间学习和工作记忆产生负面影响，并且神经服役的CNS胆碱能活性的改变将先于并与可检测的认知功能障碍相关。这些研究旨在根据其慢性影响对特定记忆的特定生物底物的慢性影响进行机械定义的研究，因为它们将有助于鉴定具有最佳影响认知功能的治疗剂，从而有可能使许多精神病患者受益。