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 precliinical model will be used to evaluate whether significant cliniclal 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 drug 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 relating 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.
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