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The involvement of the neuropeptides orexins (hypocretins) in fear and anxiety in rats exposed to a single episode of footshocks By Xiaoyu Chen A Thesis submitted to the Faculty of Graduate Studies of The University of Manitoba In partial fulfilment of the requirements of the degree of DOCTOR OF PHILOSOPHY Department of Oral Biology Faculty of Dentistry University of Manitoba Winnipeg, Manitoba Copyright © 2013 by Xiaoyu Chen Abstract Post-traumatic stress disorder (PTSD) is a psychiatric condition that can develop when people experience a stressful and life-threatening event. Clinical research indicates that the presence of a state of hyperarousal after a traumatic experience is the best predictor of a subsequent diagnosis of PTSD. The role of arousal peptides called orexins (hypocretins) in a PTSD-like condition produced by exposing rats to a single episode of footshocks (5× 2 s episodes of 1.5 mA) was investigated in this thesis. The first part of my thesis involves the characterization of the footshock model of PTSD and the second part examines the involvement of orexins in this footshock model. The following findings are reported. First, shock rats that exhibited a high level of anxiety to a novel tone (high responders, HR) the day after the footshock exposure subsequently displayed more avoidance when compared to shock rats that exhibited a low level of anxiety (low responders, LR). These results highlight the importance of individual differences in the reaction to a strong fear-inducing experience. Second, the orexin precursor peptide prepro-orexin (ppOX) mRNA was found to be elevated in rats at 6 and 14 days after exposure to footshocks. In addition, ppOX mRNA levels were found to be positively correlated with anxiety at 14 days post-shock. Third, pre-shock injections of the corticotropin releasing factor receptor antagonist antalarmin were found to attenuate the anxiety expressed to the shock chamber and eliminate the correlation between ppOX mRNA levels and anxiety. Fourth, systemic injections of the nonselective orexin receptor antagonist TCS-1102 was found to attenuate the anxiety expressed in rats at 14 days post-shock. Fifth, TCS-1102 was found to have anxiolytic effects that were specific i for the HR. The results of these experiments provide evidence linking the orexin system to the anxiety produced by exposure of rats to footshocks. They also provide preclinical evidence in support of the use of orexin antagonists for the treatment of anxiety in PTSD. ii Acknowledgements I would like to thank Dr. Gilbert J. Kirouac who gives me this opportunity to work in his laboratory and pursue my Ph.D. degree. Dr. Kirouac kindly provided academic and financial support during my graduate student period. His mentorship inspiration and efforts in interpreting data and writing have been invaluable for my research studies. I also want to give my appreciation to my lab members: Sa Li, Yonghui Li, Benjemin Rogala, Jiale Yu, and Huiying Wang who offered great help during my Ph.D. training. I would like to thank my committee members: Dr. J. Elliott Scott, Dr. Hugo T. Bergen, and Dr. Mark Fry for the guidance and insightful advices they have provided over the course of my studies. Special thank to Dr. Hugo T. Bergen who taught me how to do in situ hybridization. Great gratitude is also given towards all people Department of Oral in Biology for their friendly help. I would like to thank Faculty of Graduate Studies for the International Graduate Student Entrance Scholarships, International Graduate Student Scholarship, and the Graduate Student Travel Awards, as well as the Manitoba Health Research Council which awards me Doctoral Graduate Studentship for my doctoral studies. I want to give my great appreciation towards my mom, Guorong Chen, and my dad, Anhuai Xiong for their support and encouragement to pursue my interests. A special thank to dear Ang Gao for your love and supports. iii Dedication To my mom, Guorong Chen. 谨将此论文献给我的母亲陈国荣女士。 iv Table of Contents Abstract .......................................................................................................................... i Acknowledgements ...................................................................................................... iii Dedication .................................................................................................................... iv Table of Contents ...........................................................................................................v List of Figures ............................................................................................................. xii List of Tables...............................................................................................................xiv Abbreviations ............................................................................................................... xv Chapter 1 Introduction..................................................................................................1 1.1. General Introduction .............................................................................................1 1.2. Post-traumatic Stress Disorder (PTSD) .................................................................7 1.2.1. Symptoms and Progression ............................................................................7 1.2.2. Individual Differences in PTSD .....................................................................9 1.2.3. Fear and PTSD ............................................................................................. 11 1.2.4. HPA Axis and PTSD.................................................................................... 14 1.2.5. Exposure Therapy and Pharmacological Treatments for PTSD ..................... 17 1.2.6. Footshock Model of PTSD ........................................................................... 19 v 1.3. Orexins in the Regulation of Arousal, Stress, and Negative Emotions ................. 22 1.3.1. Orexin Peptides, Receptors, and Distribution ............................................... 22 1.3.2. Orexins in the Regulation of Arousal ............................................................ 24 1.3.3. Orexins in the Regulation of Stress .............................................................. 25 1.3.4. Orexins in the Regulation of Fear and Anxiety ............................................. 28 1.4. Objectives .......................................................................................................... 30 1.5. Hypotheses ......................................................................................................... 31 1.5.1. Hypothesis 1: Early Fear Response Predicts Anxiety.................................... 31 1.5.2. Hypothesis 2: Extinction of Fear to the Shock Chamber Attenuates Novelty Fear ........................................................................................................................ 32 1.5.3. Hypothesis 3: Footshocks Produce a Lasting Upregulation of ppOX Synthesis ............................................................................................................................... 32 1.5.4. Hypothesis 4: More Orexin Neurons are Activated in Shock Rats Placed in Situations Involving Fear. ....................................................................................... 33 1.5.5. Hypothesis 5: Blocking of CRF Receptor-1 Attenuates ppOX mRNA Synthesis and Fear Expression in Rats that Received Footshocks ............................ 34 1.5.6. Hypothesis 6: Blocking of Orexin Receptors Attenuates Fear And Anxiety ............................................................................................................................... 34 1.5.7. Hypothesis 7: Blocking of Orexin Receptors Attenuates Anxiety in a Subgroup of Shock Rats with High Levels of Anxiety ............................................ 35 vi Chapter 2 Materials and Methods .............................................................................. 36 2.1. Animals .............................................................................................................. 36 2.2. Handling and Testing ......................................................................................... 36 2.3. Footshock Procedure .......................................................................................... 37 2.4. A Rat Model of PTSD ........................................................................................ 38 2.4.1. Acute Fear Response to Novel Environment ................................................ 38 2.4.2. Fear Response to Novel Chambers and the Shock Chamber ......................... 38 2.4.3. Social Approach and Avoidance Test ........................................................... 40 2.4.4. Defensive Withdrawal Test .......................................................................... 41 2.4.5. Statistical Analysis ....................................................................................... 41 2.5. Fear Extinction Experiment ................................................................................ 42 2.5.1. Fear Extinction Training .............................................................................. 42 2.5.2. Effects of Extinction on Fear Response to Novel Environment ...................... 44 2.5.3. Statistical Analysis ....................................................................................... 45 2.6. Effects of Footshocks on ppOX mRNA Levels ..................................................
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