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 and is termed the unpredictable prenatal stress model of schizophrenia (PSup). The PSup model is ideally suited to launch a translational investigation of novel drugs for use in treating schizophrenia because the behavioral phenotype of the rats displays similarity to the behavioral symptoms of schizophrenic patients and thte enduring nature of the behavioral changes. Using the PSup animal preparation, we have generated exciting pre-clinical findings showing beneficial effects of oxytocin on social withdrawal behavior exhibited by the PSup rats. These data support the hypothesis that oxytocin may produce beneficial 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, PSup rats 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. The purpose of the Pre-clinical Studies Core is to generate the PSup rats needed to pursue the studies proposed in Project #1 of this CIDAR application and to establish the platform of behavioral outcome measures needed to evaluate the predictive validity of testing the selected compounds in the PSup animal preparation.
Showing the most recent 10 out of 22 publications
