Antipsychotics: Temporal Effects on Cognitive Function

描述（由申请人提供）：精神分裂症是一种使人衰弱的疾病，影响世界人口的1%。虽然使用抗精神病药物（精神安定药）是治疗疾病的精神病症状的标准治疗方法，但关于哪种精神安定药最适合在认知障碍患者中长期使用，我们知之甚少。精神分裂症的这一一贯特征现在被认为对该疾病的长期结局具有最实质性的影响。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制的治疗策略。本申请的目的是在实验动物模型中建立慢性精神抑制剂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，表明长期暴露于常规精神抑制剂如氟哌啶醇（以时间依赖的方式），而不是非典型药物如氯氮平，会导致认知障碍，并且胆碱能神经元的关键标志物胆碱乙酰转移酶的减少先于认知症状。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于神经营养因子、神经生长因子（NGF）的事实，我们已经发展了这样的假设，即大鼠长期暴露于常规但非典型的神经抑制剂降低了对胆碱能神经元的神经营养支持，导致脑中胆碱能活性降低和认知功能受损。拟议的动物研究的理由是，更好地了解神经阻滞剂对记忆功能的差异（慢性）影响，将有助于未来的（临床）努力，以确定最佳的药物认知受损的精神病患者。为了验证这一假设，我们提出了两个具体的目标：1）：在实验动物模型中评估不同类别的神经安定药物对认知功能的不同时间效应。（2）：确定抗精神病药诱导的认知变化与脑内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，8臂径向臂迷宫任务来评估工作记忆，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和关键胆碱能标记物的表达。我们预计，长期暴露于传统的，但不是非典型的抗精神病药物将产生负面影响的空间学习和工作记忆和抗精神病药物诱导的中枢神经系统胆碱能活性的改变将之前和相关的可检测的表现认知功能障碍。这些研究，旨在机械地定义神经阻滞剂的基础上，其对特定的生物基质的记忆的慢性影响是显着的，因为它们将有助于识别的治疗剂与认知功能的最佳效果，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.