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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Special Emphasis Panel (ZMH1)
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University of Maryland Baltimore
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Carpenter Jr, William T; Buchanan, Robert W (2017) Negative Symptom Therapeutics. Schizophr Bull 43:681-682
Buchanan, Robert W; Kelly, Deanna L; Weiner, Elaine et al. (2017) A Randomized Clinical Trial of Oxytocin or Galantamine for the Treatment of Negative Symptoms and Cognitive Impairments in People With Schizophrenia. J Clin Psychopharmacol 37:394-400
Cohen, Alex S; Mitchell, Kyle R; Strauss, Gregory P et al. (2017) The effects of oxytocin and galantamine on objectively-defined vocal and facial expression: Data from the CIDAR study. Schizophr Res 188:141-143
Lee, Mary R; Wehring, Heidi J; McMahon, Robert P et al. (2016) Relationship of plasma oxytocin levels to baseline symptoms and symptom changes during three weeks of daily oxytocin administration in people with schizophrenia. Schizophr Res 172:165-8
Strauss, Gregory P; Keller, William R; Koenig, James I et al. (2015) Endogenous oxytocin levels are associated with the perception of emotion in dynamic body expressions in schizophrenia. Schizophr Res 162:52-6
Strauss, Gregory P; Keller, William R; Koenig, James I et al. (2015) Plasma oxytocin levels predict olfactory identification and negative symptoms in individuals with schizophrenia. Schizophr Res 162:57-61
Strauss, Gregory P; Keller, William R; Koenig, James I et al. (2015) Plasma oxytocin levels predict social cue recognition in individuals with schizophrenia. Schizophr Res 162:47-51
Wilson, Christina A; Koenig, James I (2014) Social interaction and social withdrawal in rodents as readouts for investigating the negative symptoms of schizophrenia. Eur Neuropsychopharmacol 24:759-73
Schulz, Kalynn M; Andrud, Kristin M; Burke, Maria B et al. (2013) The effects of prenatal stress on alpha4 beta2 and alpha7 hippocampal nicotinic acetylcholine receptor levels in adult offspring. Dev Neurobiol 73:806-14
Braff, David L; Ryan, James; Rissling, Anthony J et al. (2013) Lack of use in the literature from the last 20 years supports dropping traditional schizophrenia subtypes from DSM-5 and ICD-11. Schizophr Bull 39:751-3

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