Centers for Intervention Development and Applied Research (CIDAR)

项目1：评估催产素在精神分裂症产前应激动物模型中的作用（PI: James Koenig博士）。精神分裂症的药物开发一直以精神病为导向，但原发性阴性症状和认知障碍与不良的功能预后密切相关。这个CIDAR应用包含了新的临床前和临床方法对于精神分裂症阴性症状和认知障碍领域的新疗法的开发是必要的。我们已经根据发育和流行病学数据生成了一种新的临床前动物制剂，这些数据显示妊娠中期应激暴露会增加患精神分裂症的风险。这种临床前模型非常适合于开展用于治疗精神分裂症的新药的转化研究。使用该模型获得的令人兴奋的临床前发现，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，正如本CIDAR应用和项目#1、2和3中提出的那样。此外，该临床前模型将用于评估关于α ？烟碱受体与认知可以延伸到临床前的情况。

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.