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Effects of Omega-3 Fatty Acids on Rodent Models of Bipolar Disorder and Alcoholism

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Effects of Omega-3 Fatty Acids on Rodent Models of Bipolar Disorder and Alcoholism EFFECTS OF OMEGA-3 FATTY ACIDS ON RODENT MODELS OF BIPOLAR DISORDER AND ALCOHOLISM Natalie J. Case Submitted to the faculty of the University Graduate School in partial fulfillment of the requirements for the degree Master of Science in the Program of Medical Neuroscience Indiana University May 2010 Accepted by the Faculty of Indiana University, in partial fulfillment of the requirements for the degree of Master of Science. ___________________________________ Gerry S. Oxford, PhD, Chair ___________________________________ Alexander B. Niculescu, III, MD, PhD Master’s Thesis Committee ___________________________________ Cristine L. Czachowski, PhD ii ACKNOWLEDGEMENTS I would like to express sincere appreciation to my advisor on this project and committee member, Alexander B. Niculescu, III, MD, PhD, and to my advisor and committee chair, Gerry S. Oxford, PhD, for their guidance and support in conducting research and while writing this thesis. I would also like to thank my committee member, Cristine L. Czachowski, PhD, for her guidance in writing and Zachary A. Rodd, PhD for his help in evaluating results. My thanks and appreciation go to Helen Le-Niculescu, PhD as she directed the research work for the previous paper and the current study presented in this thesis, and I thank fellow lab member, Sagar Patel, for his dedicated work on this research project. To my husband Joshua, I give sincere gratitude for his love, support, and encouragement throughout my work on this research. iii TABLE OF CONTENTS List of Tables .......................................................................................................................v List of Figures.................................................................................................................... vi List of Abbreviations ........................................................................................................ vii Chapter I: Introduction and Background .............................................................................1 Bipolar Disorder.......................................................................................................1 Omega-3 Fatty Acids ...............................................................................................5 Previous Studies.......................................................................................................8 Background of Present Study.................................................................................16 Chapter II: Manuscript.......................................................................................................20 Introduction............................................................................................................21 Materials and Methods...........................................................................................23 Results....................................................................................................................33 Discussion..............................................................................................................66 Conclusion .............................................................................................................74 Chapter III: Implications and Future Directions................................................................75 Literature Cited ..................................................................................................................84 Curriculum Vitae iv LIST OF TABLES Table 1. Top ST DBP KO gene expression changes in female mice on high DHA vs. low DHA diet.............................................................................40 Table 2. Top ST DBP KO gene expression changes in male mice on high DHA vs. low DHA diet.............................................................................51 Table 3. Ingenuity pathway analysis of top candidate genes.............................................61 v LIST OF FIGURES Figure 1. The arachidonic acid (AA) cascade and how drugs prescribed to fight bipolar disorder modulate the cascade ........................................................4 Figure 2. Genetic and environmental factors related to omega-3 fatty acid and omega-6 fatty acid involvement in biological processes and dysfunctions.....................................................................7 Figure 3. Phenomics of ST DBP KO mice: locomotion, switch, sleep deprivation, clustering..................................................12 Figure 4. Ethanol consumption during the stress paradigm in DBP KO and WT mice ..........................................................................................15 Figure 5. Effects of DHA on ST DBP KO and ST WT mice behavior .............................35 Figure 6. Expanded Convergent Functional Genomics (CFG) analysis............................39 Figure 7. Top candidate genes changes in ST DBP KO mice on high vs. low DHA diet ......................................................................................57 Figure 8. Effects of DHA on ethanol consumption in male ST DBP KO mice......................................................................................64 Figure 9. Effects of DHA on ethanol consumption in male alcohol-preferring (P) rats.........................................................................65 Figure 10. High DHA diet has a stabilizing effect on mood in ST DBP KO and WT mice .................................................................68 vi LIST OF ABBREVIATIONS AA arachidonic acid CFG Convergent Functional Genomics DBP D-box Binding Protein EPA eicosapentaenoic acid KO knockout NST non-stressed PFC prefrontal cortex PUFA polyunsaturated fatty acid QTL Quantitative Trait Loci ST stressed TG transgenic WT wild-type vii CHAPTER I: INTRODUCTION AND BACKGROUND Bipolar Disorder Bipolar disorder is a debilitating illness that affects more than 3 million adult Americans [1]. People with this disease experience severe fluctuations in mood, from a very high-energy, manic state to a low-energy, depressed state. During manic states they are known to become impulsive and highly irritable, and experience racing thoughts, excessive talkativeness and decreased sleep. Sometimes suddenly they can transition to a depressed state with symptoms including increased feelings of hopelessness and sorrow, lack of energy, increased sleep, and thoughts of suicide. Indeed, lifetime incidence of suicide for bipolar patients is between 10-20% [2]. There are subsets of the disorder, with bipolar I consisting of repeated cycles of depressive and manic episodes, and bipolar II consisting of depressive and hypomanic episodes [2]. Episodes can last for days, months, or even years [1]. Bipolar disorder usually develops in late adolescence and early adulthood and without treatment can persist until death. This disorder also has a high rate of co-morbidity with alcoholism, leading to further destructive behavior [3]. The mechanisms underlying bipolar disorder are currently unknown. However, research has shown that this disorder is correlated with dysregulation in the dopamine and serotonin systems, as well as with pathology in the brain systems associated with regulating emotions [4]. When there is an excess of dopamine or serotonin, manic behavior, such as excessive talkativeness, impulsivity, irritability, and less need for sleep, is induced. When there is a deficiency in these amines, depressive mood and behavior, such as excessive need for sleep, and feelings of sorrow, helplessness, and worthlessness, are induced [1]. Other studies suggest that upregulation of the arachidonic acid (AA) 1 cascade is involved in the development of bipolar disorder. AA is an essential long-chain polyunsaturated fatty acid (PUFA), specifically an omega-6 fatty acid, that is involved in brain signaling via sertonergic, glutamatergic, dopaminergic, and cholinergic receptor stimulation [5]. Upregulation of the AA cascade can induce inflammation and neurological dysfunctions which have been implicated in bipolar disorder [6]. Drug treatment for bipolar disorder has been employed since the early 1950s with the discovery that lithium could stabilize mood [7]. Currently, drugs such as lithium, valproate, and carbamazepine are used to treat the symptoms of bipolar disorder. Interestingly, it has been shown that these drugs modulate the AA turnover rate in the brain. The AA cascade begins with phospholipase A 2 (PLA 2) hydrolyzing esterified AA from membrane phospholipids [5]. Long-chain acyl-CoA synthetases (Acsls) and acyl transferase reincorporate a majority of the released AA into brain phospholipids, while enzymes such as cyclooxygenases (COX) convert a small amount of the released AA into eicosanoids. Using radiolabeled fatty acid and quantitative autoradiographic analysis, incorporation rates of plasma unesterified AA into brain phospholipids can be determined in rodents [8]. Using these techniques, Chang et al. showed that chronic intake of lithium decreased AA turnover within the brain of rats by decreasing brain COX-2 activity and inhibiting the transcription of cPLA 2, which is the AA-selective calcium-dependent cytosolic form of PLA 2 [9]. Likewise, carbamazepine also decreases the turnover rate of AA in the rodent brain by decreasing COX-2 activity and inhibiting transcription of cPLA 2 [10]. Valproic acid also decreases the turnover rate of AA in the rodent brain, however, it appears to do so by inhibiting Acsl [11] and prevents nuclear factor-κB (NF κB) from inducing the transcription
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