Antipsychotics: Temporal Effects on Cognitive Function

描述(申请人提供)：精神分裂症是一种使人衰弱的疾病，影响多达1%的世界人口。虽然使用抗精神病药物(抗精神病药物)是治疗疾病精神症状的标准护理，但对于哪些神经抗精神病药物在认知障碍患者中延长使用时间最好，人们知之甚少。精神分裂症的这种始终如一的特征现在被认为对疾病的长期结果产生了最实质性的影响。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。这项应用的目的是在一个实验动物模型中建立长期接触抗精神病药物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常规抗精神病药物(以时间依赖的方式)，而不是氯氮平等非典型药物，会导致认知障碍，而且胆碱能神经元的关键标志胆碱乙酰转移酶的降低会先于认知症状。由于胆碱能酶染色减少的模式以及参与学习和记忆的许多胆碱能神经元在功能上依赖神经营养因子神经生长因子(NGF)的事实，我们提出了一种假说，即大鼠长期接触常规的但不是非典型的抗精神病药物会减少对胆碱能神经元的神经营养支持，导致大脑中胆碱能活性的降低和认知功能的损害。拟议的动物研究的基本原理是，更好地了解神经镇静剂对记忆功能的不同(慢性)影响将有助于未来(临床)努力为认知受损的精神疾病患者寻找最佳药物。为了验证这一假设，我们提出了两个具体的目标：1)在一个实验动物模型中，评估不同类别的抗精神病药物对认知功能的不同时间效应。2)：明确抗精神病药引起的认知改变与脑内胆碱能功能生化和细胞参数、神经生长因子释放和神经生长因子受体表达的时间变化之间的潜在相关性。我们将使用水迷宫任务来测量空间学习，使用八臂径向臂迷宫任务来评估工作记忆，并使用原位杂交、Western blotts、ELISA实验、免疫荧光染色和受体放射自显影来测量NGF和关键胆碱能标志的表达。我们预计，长期使用常规但不是非典型的抗精神病药物将对空间学习和工作记忆产生负面影响，并且由抗精神病药物引起的中枢神经系统胆碱能活动的改变将先于认知功能障碍的可察觉表现并与其相关。这些研究旨在根据对记忆的特定生物底物的慢性影响来机械地定义抗精神病药物，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。

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.