Brain Fatty Acid Composition and PKC Activity

Summary

Principal Investigator: Robert K McNamara
Abstract: [unreadable] DESCRIPTION (provided by applicant): Current first-line mood-stabilizer and atypical antipsychotic drugs used in the treatment of bipolar disorder and schizophrenia have limited long-term prophylactic efficacy in 30-40 percent of patients, and several adverse side-effects which frequently lead to additional health-related problems and/or patient noncompliance and relapse. There is therefore an urgent need for the development and validation of new treatments with improved long-term efficacy, safety, and tolerability. Chronic, but not acute, treatment with mood-stabilizer and antipsychotic drugs at therapeutically-relevant concentrations down-regulate protein kinase C (PKC) activity and isozyme expression in rat brain. The principle omega-3 fatty acid found in brain, docosahexaenoic acid (DHA), is derived exclusively from the diet, is specifically enriched in neuronal synaptic membranes, and inhibits PKC in vitro. However, there currently exists a significant knowledge gap in our understanding of the consequences of altering synaptic DHA composition on PKC activity/expression in brain. The primary objective of this proposal is to determine if systematic alterations (increases and decreases) in brain DHA concentrations through dietary manipulations can modulate PKC activity/expression in brain. Our primary HYPOTHESIS is that reductions or elevations in brain DHA concentrations will increase and decrease, respectively, PKC activity/expression. We will also determine if alterations in brain DHA concentrations can modulate the dopamine D2 receptor, a clinically-relevant substrate of PKC. We anticipate that the proposed studies will provide 'proof-of-concept' data demonstrating that dietary-induced reductions/elevations in brain DHA concentrations will increase/decrease PKC activity (SA1) and decrease/increase D2 receptor binding (SA2) in a DHA-concentration-dependent manner. Predicative validity will be evaluated by determining if dietary-induced elevations in PKC activity and reductions in D2 receptor binding can be reversed (normalized) by chronic, but not acute, treatment with haloperidol, olanzapine, lithium, or DHA-rich diets (SA3). The anticipated results will provide a strong scientific foundation and rationale to perform analogous studies in human subjects using in vivo imaging. The proposed experiments are innovative and exploratory in that the effect of altered DHA concentrations on PKC and dopamine D2 receptor expression have not been systematically examined in brain. [unreadable] [unreadable] [unreadable]
Funding Period: 2006-08-01 - 2008-07-31
more information: NIH RePORT

Top Publications

  1. pmc Abnormal fatty acid pattern in the superior temporal gyrus distinguishes bipolar disorder from major depression and schizophrenia and resembles multiple sclerosis
    Robert K McNamara
    Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA Electronic address
    Psychiatry Res 215:560-7. 2014
  2. pmc 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
    Jessica A Able
    Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
    J Psychiatr Res 50:42-50. 2014
  3. pmc 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
    Robert K McNamara
    Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH 45267, United States Electronic address
    Pharmacol Biochem Behav 114:1-8. 2013
  4. pmc Docosahexaenoic acid supplementation increases prefrontal cortex activation during sustained attention in healthy boys: a placebo-controlled, dose-ranging, functional magnetic resonance imaging study
    Robert K McNamara
    Department of Psychiatry, Center for Imaging Research, Division of Bipolar Disorders Research, University of Cincinnati College of Medicine, Cincinnati, OH 45219 0516, USA
    Am J Clin Nutr 91:1060-7. 2010
  5. pmc Elevated Delta-6 desaturase (FADS2) gene expression in the prefrontal cortex of patients with bipolar disorder
    Yanhong Liu
    Department of Psychiatry, Division of Bipolar Disorders Research, University of Cincinnati College of Medicine, 260 Stetson Street, Suite 3306, Cincinnati, OH 45219, USA
    J Psychiatr Res 45:269-72. 2011
  6. pmc Effect of chronic fluoxetine treatment on male and female rat erythrocyte and prefrontal cortex fatty acid composition
    Robert K McNamara
    Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
    Prog Neuropsychopharmacol Biol Psychiatry 34:1317-21. 2010
  7. pmc Omega-3 fatty acid deficiency increases constitutive pro-inflammatory cytokine production in rats: relationship with central serotonin turnover
    Robert K McNamara
    Department of Psychiatry, University of Cincinnati College of Medicine, 260 Stetson Street, Suite 3306, Cincinnati, OH 45219 0516, USA
    Prostaglandins Leukot Essent Fatty Acids 83:185-91. 2010
  8. pmc Reduced expression of fatty acid biosynthesis genes in the prefrontal cortex of patients with major depressive disorder
    Robert K McNamara
    Department of Psychiatry, Lipidomics Research Program, University of Cincinnati College of Medicine, Cincinnati, OH 45219, United States
    J Affect Disord 129:359-63. 2011
  9. ncbi Evaluation of docosahexaenoic acid deficiency as a preventable risk factor for recurrent affective disorders: current status, future directions, and dietary recommendations
    Robert K McNamara
    Department of Psychiatry, Division of Bipolar Disorders Research, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
    Prostaglandins Leukot Essent Fatty Acids 81:223-31. 2009
  10. ncbi Elevated delta-6 desaturase (FADS2) expression in the postmortem prefrontal cortex of schizophrenic patients: relationship with fatty acid composition
    Yanhong Liu
    Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267, United States
    Schizophr Res 109:113-20. 2009

Scientific Experts

Detail Information

Publications25

  1. pmc Abnormal fatty acid pattern in the superior temporal gyrus distinguishes bipolar disorder from major depression and schizophrenia and resembles multiple sclerosis
    Robert K McNamara
    Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA Electronic address
    Psychiatry Res 215:560-7. 2014
    ..Collectively, these data demonstrate that BD patients exhibit a pattern of fatty acid abnormalities in the STG that is not observed in MDD and SZ patients and closely resembles MS patients. ..
  2. pmc 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
    Jessica A Able
    Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
    J Psychiatr Res 50:42-50. 2014
    ..These preclinical data demonstrate that low omega-3 fatty acid status leads to abnormal behavioral and neurochemical responses to chronic FLX treatment in male rats. ..
  3. pmc 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
    Robert K McNamara
    Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, OH 45267, United States Electronic address
    Pharmacol Biochem Behav 114:1-8. 2013
    ..These preclinical data demonstrate that n-3 fatty acid deficiency does not significantly reduce the effects of chronic FLX treatment on central 5-HT turnover or behavior in the FST in female rats. ..
  4. pmc Docosahexaenoic acid supplementation increases prefrontal cortex activation during sustained attention in healthy boys: a placebo-controlled, dose-ranging, functional magnetic resonance imaging study
    Robert K McNamara
    Department of Psychiatry, Center for Imaging Research, Division of Bipolar Disorders Research, University of Cincinnati College of Medicine, Cincinnati, OH 45219 0516, USA
    Am J Clin Nutr 91:1060-7. 2010
    ..However, the effects of DHA supplementation on functional cortical activity in human subjects are unknown...
  5. pmc Elevated Delta-6 desaturase (FADS2) gene expression in the prefrontal cortex of patients with bipolar disorder
    Yanhong Liu
    Department of Psychiatry, Division of Bipolar Disorders Research, University of Cincinnati College of Medicine, 260 Stetson Street, Suite 3306, Cincinnati, OH 45219, USA
    J Psychiatr Res 45:269-72. 2011
    ....
  6. pmc Effect of chronic fluoxetine treatment on male and female rat erythrocyte and prefrontal cortex fatty acid composition
    Robert K McNamara
    Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
    Prog Neuropsychopharmacol Biol Psychiatry 34:1317-21. 2010
    ..These preclinical findings do not support the hypothesis that chronic FLX treatment increases n-3 fatty acid biosynthesis or membrane composition...
  7. pmc Omega-3 fatty acid deficiency increases constitutive pro-inflammatory cytokine production in rats: relationship with central serotonin turnover
    Robert K McNamara
    Department of Psychiatry, University of Cincinnati College of Medicine, 260 Stetson Street, Suite 3306, Cincinnati, OH 45219 0516, USA
    Prostaglandins Leukot Essent Fatty Acids 83:185-91. 2010
    ..These preclinical data provide evidence for a functional link between n-3 fatty acid deficiency, elevated peripheral inflammatory signaling, and increased central 5-HT turnover...
  8. pmc Reduced expression of fatty acid biosynthesis genes in the prefrontal cortex of patients with major depressive disorder
    Robert K McNamara
    Department of Psychiatry, Lipidomics Research Program, University of Cincinnati College of Medicine, Cincinnati, OH 45219, United States
    J Affect Disord 129:359-63. 2011
    ..However, the etiology of these deficits remains poorly understood, and there is currently little known about the expression of genes that mediate fatty acid biosynthesis in MDD patients...
  9. ncbi Evaluation of docosahexaenoic acid deficiency as a preventable risk factor for recurrent affective disorders: current status, future directions, and dietary recommendations
    Robert K McNamara
    Department of Psychiatry, Division of Bipolar Disorders Research, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
    Prostaglandins Leukot Essent Fatty Acids 81:223-31. 2009
    ..Such early intervention studies are currently feasible and will ultimately be required to definitively evaluate whether DHA is a required nutrient for the prevention of affective disorders...
  10. ncbi Elevated delta-6 desaturase (FADS2) expression in the postmortem prefrontal cortex of schizophrenic patients: relationship with fatty acid composition
    Yanhong Liu
    Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267, United States
    Schizophr Res 109:113-20. 2009
    ..Greater Delta6 desaturase expression and activity could have implications for central prostaglandin synthesis and proinflammatory signaling...
  11. ncbi Fatty acid composition of the postmortem prefrontal cortex of adolescent male and female suicide victims
    Robert K McNamara
    Department of Psychiatry, University of Cincinnati College of Medicine, Medical Science Building, 231 Albert Sabin Way, Cincinnati, OH 45267 0559, USA
    Prostaglandins Leukot Essent Fatty Acids 80:19-26. 2009
    ....
  12. pmc Gender differences in rat erythrocyte and brain docosahexaenoic acid composition: role of ovarian hormones and dietary omega-3 fatty acid composition
    Robert K McNamara
    Department of Psychiatry, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267 0516, United States
    Psychoneuroendocrinology 34:532-9. 2009
    ....
  13. pmc Chronic risperidone treatment preferentially increases rat erythrocyte and prefrontal cortex omega-3 fatty acid composition: evidence for augmented biosynthesis
    Robert K McNamara
    Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267 0559, United States
    Schizophr Res 107:150-7. 2009
    ..Augmented omega-3 fatty acid biosynthesis and membrane composition represents a novel mechanism of action that may contribute in part to the efficacy of RISP in the treatment of SZ...
  14. pmc Omega-3 fatty acid deficiency during perinatal development increases serotonin turnover in the prefrontal cortex and decreases midbrain tryptophan hydroxylase-2 expression in adult female rats: dissociation from estrogenic effects
    Robert K McNamara
    Department of Psychiatry, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati OH 45267 0559, United States
    J Psychiatr Res 43:656-63. 2009
    ..03). These preclinical data support a causal link between perinatal omega-3 fatty acid deficiency and reduced central serotonin synthesis in adult female rats that is independent of ovarian hormones including estrogen...
  15. ncbi Modulation of phosphoinositide-protein kinase C signal transduction by omega-3 fatty acids: implications for the pathophysiology and treatment of recurrent neuropsychiatric illness
    Robert K McNamara
    Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267 0559, USA
    Prostaglandins Leukot Essent Fatty Acids 75:237-57. 2006
    ..The data reviewed in this paper outline a potential molecular mechanism by which omega-3 fatty acids could contribute to the pathophysiology and treatment of recurrent neuropsychiatric illness...
  16. ncbi Role of omega-3 fatty acids in brain development and function: potential implications for the pathogenesis and prevention of psychopathology
    Robert K McNamara
    Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267 0559, USA
    Prostaglandins Leukot Essent Fatty Acids 75:329-49. 2006
    ....
  17. ncbi Selective deficits in the omega-3 fatty acid docosahexaenoic acid in the postmortem orbitofrontal cortex of patients with major depressive disorder
    Robert K McNamara
    Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267 0559, USA
    Biol Psychiatry 62:17-24. 2007
    ..It was hypothesized that patients with MDD would exhibit lower frontal cortical concentrations of docosahexaenoic acid (DHA), the principal omega-3 fatty acid in brain, relative to normal controls...
  18. pmc Abnormalities in the fatty acid composition of the postmortem orbitofrontal cortex of schizophrenic patients: gender differences and partial normalization with antipsychotic medications
    Robert K McNamara
    Department of Psychiatry, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267 0559, United States
    Schizophr Res 91:37-50. 2007
    ....
  19. ncbi Omega-3 fatty acid deficiency augments amphetamine-induced behavioral sensitization in adult mice: prevention by chronic lithium treatment
    Robert K McNamara
    Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267, United States
    J Psychiatr Res 42:458-68. 2008
    ....
  20. pmc The aging human orbitofrontal cortex: decreasing polyunsaturated fatty acid composition and associated increases in lipogenic gene expression and stearoyl-CoA desaturase activity
    Robert K McNamara
    Department of Psychiatry, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, USA
    Prostaglandins Leukot Essent Fatty Acids 78:293-304. 2008
    ..The implications of age-related reductions in OFC PUFA composition for affective dysregulation in the elderly are discussed...
  21. ncbi Omega-3 fatty acid deficiency augments amphetamine-induced behavioral sensitization in adult DBA/2J mice: relationship with ventral striatum dopamine concentrations
    Robert K McNamara
    Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA
    Synapse 62:725-35. 2008
    ....
  22. pmc Deficits in docosahexaenoic acid and associated elevations in the metabolism of arachidonic acid and saturated fatty acids in the postmortem orbitofrontal cortex of patients with bipolar disorder
    Robert K McNamara
    Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
    Psychiatry Res 160:285-99. 2008
    ..low alcohol abuse severity. These results add to a growing body of evidence implicating omega-3 fatty acid deficiency as well as the OFC in the pathoaetiology of bipolar disorder...
  23. pmc Perinatal n-3 fatty acid deficiency selectively reduces myo-inositol levels in the adult rat PFC: an in vivo (1)H-MRS study
    Robert K McNamara
    Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
    J Lipid Res 50:405-11. 2009
    ..02). These data demonstrate that perinatal deficits in cortical DHA accrual significantly and selectively reduce mI concentrations and augment receptor-generated mI synthesis...
  24. ncbi Inbred C57BL/6J and DBA/2J mouse strains exhibit constitutive differences in regional brain fatty acid composition
    Robert K McNamara
    Department of Psychiatry, University of Cincinnati College of Medicine, Cincinnati, OH 45267 0516, USA
    Lipids 44:1-8. 2009
    ....
  25. ncbi The emerging role of omega-3 fatty acids in psychiatry
    Robert K McNamara
    Prostaglandins Leukot Essent Fatty Acids 75:223-5. 2006