Schizophrenia negatively impacts the lives of approximately 3 million Americans, and represents a major global health burden. The identification of susceptibility factors relevant to the pathogenesis of schizophrenia in conjunction with animal modelling will likely accelerate the development of novel treatment strategies with improved efficacy, safety, and tolerability. There is a beurgoning body of evidence from epidemiological, clinical, neuroanatomical, neurochemical, and neurodevelopmental studies that implicate omega-3 (n-3) fatty acid deficiency as an important susceptibility factor in schizophrenia pathogenesis. The objective of this application is to test the central hypothesis that n-3 fatty acid deficiency will reproduce in rats the neuroanatomical, behavioral, and neurochemical abnormalities observed in other putative animal models of schizophrenia. The rationale for the proposed studies is that their completion is anticipated to produce proof- of-concept data regarding the face, construct, and predictive validity of a novel animal model of schizophrenia. The model's face and construct validity will be evaluated by determining the effect of n-3 fatty acid deficiency in rat on: (1) neuroanatomical features by magnetic resonance imaging: volume reductions in white matter, gray matter, amygdala-hippocampus complex, thalamus, cerebellar vermis, and corpus callossum volume, volume increases in lateral and third ventricular, and basal ganglia, and postmortem regional reductions in N-acetyl aspartate levels (Specific Aim 1), (2) behavioral/neuropsychological features: latent inhibition (attention), prepulse inhibition (sensorimotor gating), hippocampus- and prefrontal cortex- dependent learning (declarative and working memory), social interaction (social withdrawal), and sucrose preference (anhedonia)(Specific Aim 2), and (3) neurochemical features: increased sensitivity to dopamine- agonist- (amphetamine) and the NMDA receptor antagonist- (MK-801) induced locomotor activity and stereotypy (Specific Aim 3). The model's predictive validity will be evaluated by determining the capacity of prior chronic antipsychotic treatment to attenuate n-3 fatty acid deficiency-induced deficits. These experiments are innovative and the results will be significant because they are anticipated to establish the face, construct, and predictive validity of a novel animal model of schizophrenia created via the manipulation of a candidate non-genomic susceptibility factor, n-3 fatty acid deficiency. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH073704-01A1
Application #
7048319
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Meinecke, Douglas L
Project Start
2006-02-01
Project End
2008-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
1
Fiscal Year
2006
Total Cost
$207,225
Indirect Cost
Name
University of Cincinnati
Department
Psychiatry
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
McNamara, Robert K; Rider, Therese; Jandacek, Ronald et al. (2014) Abnormal fatty acid pattern in the superior temporal gyrus distinguishes bipolar disorder from major depression and schizophrenia and resembles multiple sclerosis. Psychiatry Res 215:560-7
Able, Jessica A; Liu, Yanhong; Jandacek, Ronald et al. (2014) Omega-3 fatty acid deficient male rats exhibit abnormal behavioral activation in the forced swim test following chronic fluoxetine treatment: association with altered 5-HT1A and alpha2A adrenergic receptor expression. J Psychiatr Res 50:42-50
McNamara, Robert K; Able, Jessica A; Liu, Yanhong et al. (2013) Omega-3 fatty acid deficiency does not alter the effects of chronic fluoxetine treatment on central serotonin turnover or behavior in the forced swim test in female rats. Pharmacol Biochem Behav 114-115:1-8
McNamara, Robert K; Jandacek, Ronald; Rider, Therese et al. (2011) Atypical antipsychotic medications increase postprandial triglyceride and glucose levels in male rats: relationship with stearoyl-CoA desaturase activity. Schizophr Res 129:66-73
McNamara, Robert K; Jandacek, Ronald; Rider, Therese et al. (2011) Differential effects of antipsychotic medications on polyunsaturated fatty acid biosynthesis in rats: Relationship with liver delta6-desaturase expression. Schizophr Res 129:57-65
Liu, Yanhong; McNamara, Robert K (2011) Elevated Delta-6 desaturase (FADS2) gene expression in the prefrontal cortex of patients with bipolar disorder. J Psychiatr Res 45:269-72
McNamara, Robert K; Jandacek, Ronald; Rider, Therese et al. (2011) Chronic risperidone normalizes elevated pro-inflammatory cytokine and C-reactive protein production in omega-3 fatty acid deficient rats. Eur J Pharmacol 652:152-6
McNamara, Robert K; Liu, Yanhong (2011) Reduced expression of fatty acid biosynthesis genes in the prefrontal cortex of patients with major depressive disorder. J Affect Disord 129:359-63
McNamara, Robert K; Able, Jessica A; Rider, Therese et al. (2010) Effect of chronic fluoxetine treatment on male and female rat erythrocyte and prefrontal cortex fatty acid composition. Prog Neuropsychopharmacol Biol Psychiatry 34:1317-21
McNamara, Robert K; Jandacek, Ronald; Rider, Therese et al. (2010) Omega-3 fatty acid deficiency increases constitutive pro-inflammatory cytokine production in rats: relationship with central serotonin turnover. Prostaglandins Leukot Essent Fatty Acids 83:185-91

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