Centers for Intervention Development and Applied Research (CIDAR)

描述(由申请人提供)：项目1：在精神分裂症的产前应激动物模型中评估催产素(PI：James Koenig博士)。治疗精神分裂症的药物发现一直是针对精神病的，但主要的阴性症状和认知障碍与不良的功能结果密切相关。这种CIDAR应用包含这样的概念，即新的临床前和临床方法对于开发针对精神分裂症的阴性症状和认知障碍领域的新疗法是必要的。我们基于发育和流行病学数据产生了一种新的临床前动物制剂，表明孕中期应激暴露会增加患精神分裂症的风险。这一临床前模型非常适合于启动用于治疗精神分裂症的新药的翻译研究。使用该模型的令人振奋的临床前发现为研究催产素在精神分裂症阴性症状的临床和临床前模型中的作用奠定了基础，如在CIDAR应用和项目1、2和3中所建议的。此外，该临床前模型将被用于评估关于阿尔法？烟碱受体和认知可以扩展到临床前的情况。 CIDAR应用的总体假设框架基于以下命题：1)阴性症状和认知障碍可能是药物开发的单独临床靶点，对一个领域有效的药物可能不会对另一个领域产生影响；2)临床试验中某个领域的药物效果将与临床前大鼠模型和非临床人类模型中的类似效果相关；3)催产素受体刺激和α-7尼古丁受体刺激将分别有利于与精神分裂症阴性症状和认知障碍相关的行为。我们将在临床前大鼠模型中检验以下假设：假设1A：催产素将改善与精神分裂症阴性症状相关的行为，但不会改善临床前大鼠模型中的认知障碍。假设1B：在临床前大鼠模型中，社会功能的改善将伴随着催产素mRNA生产和受体功能的正常化。假设2A：用α-7尼古丁受体部分激动剂DMXB-A刺激α-7尼古丁受体将改善临床前大鼠模型的认知能力，但不会改善与疾病阴性症状相关的行为分析。假设2B：认知的改善将伴随着临床前模型大鼠海马区α-7尼古丁受体表达的增加。本项目的数据也将被用来解决CIDAR的总体假设。

DESCRIPTION (provided by applicant): Project 1: Evaluation of Oxytocin in the Prenatal Stress Animal Model of Schizophrenia (PI: Dr. James Koenig). Drug discovery for schizophrenia has been oriented towards psychosis, but primary negative symptoms and the cognitive impairments are robustly associated with poor functional outcomes. This CIDAR application embraces the notion that novel preclinical and clinical approaches are necessary for the development of new therapies for the negative symptom and cognitive impairment domains of schizophrenia. We have generated a novel pre-clinical animal preparation based on developmental and epidemiological data showing that mid-gestational stress exposure increases the risk for developing schizophrenia. This preclinical model is ideally suited to launch a translational investigation of novel drugs for use in treating schizophrenia. Exciting pre-clinical findings from the use of this model form the basis for studying oxytocin's effects in clinical and pre-clinical models of the negative symptoms of schizophrenia, as proposed in this CIDAR application and in Projects #1, 2 and 3. Additionally, this preclinical model will be used to evaluate whether significant clinical findings regarding the alpha? nicotinic receptor and cognition can be extended to the pre-clinical situation. The overall hypothetical framework for this CIDAR application is based on the following propositions: 1) that negative symptoms and cognitive impairments may be separate clinical targets for drug development, and a 0drug with efficacy for one domain may not have an effect on the other; 2) that a drug effect on a domain in a clinical trial will be associated with a similar effect in a pre-clinical rat model and a non-clinical human model and 3) that oxytocin receptor stimulation and alpha-7 nicotinic receptor stimulation will benefit behaviors elating to the negative symptoms and cognitive impairments of schizophrenia, respectively. We will examine the following hypotheses in the pre-clinical rat model: hypothesis 1 A: oxytocin will improve behaviors related to the negative symptoms of schizophrenia but not the cognitive impairments in the pre-clinical rat model of schizophrenia. Hypothesis 1B: improvement of social function in the pre-clinical rat model will be accompanied by normalization of oxytocin mRNA production and receptor function. Hypothesis 2A: alpha-7 nicotinic receptor stimulation with DMXB-A, an alpha-7 nicotinic receptor partial agonist, will improve cognition in the pre-clinical rat model but not behavioral assays related to the negative symptoms of the disease. Hypothesis 2B: improvements in cognition will be accompanied by increased expression of alpha-7 nicotinic receptors in the hippocampus of the rat pre-clinical model. Data from this Project will also be used to address the overall CIDAR hypotheses.