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The Involvement of Sigma Receptor Modulation in the Antidepressant Effects of Ketamine and the Neurotoxic Actions of Methamphetamine Graduate Theses, Dissertations, and Problem Reports 2013 The Involvement of Sigma Receptor Modulation in the Antidepressant Effects of Ketamine and the Neurotoxic Actions of Methamphetamine Matthew J. Robson West Virginia University Follow this and additional works at: https://researchrepository.wvu.edu/etd Recommended Citation Robson, Matthew J., "The Involvement of Sigma Receptor Modulation in the Antidepressant Effects of Ketamine and the Neurotoxic Actions of Methamphetamine" (2013). Graduate Theses, Dissertations, and Problem Reports. 3661. https://researchrepository.wvu.edu/etd/3661 This Dissertation is protected by copyright and/or related rights. It has been brought to you by the The Research Repository @ WVU with permission from the rights-holder(s). You are free to use this Dissertation in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you must obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This Dissertation has been accepted for inclusion in WVU Graduate Theses, Dissertations, and Problem Reports collection by an authorized administrator of The Research Repository @ WVU. For more information, please contact [email protected]. The Involvement of Sigma Receptor Modulation in the Antidepressant Effects of Ketamine and the Neurotoxic Actions of Methamphetamine Matthew J. Robson A dissertation submitted to the School of Pharmacy at West Virginia University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pharmaceutical and Pharmacological Sciences Rae R. Matsumoto, Ph.D., Chair Jason D. Huber, Ph.D. James O’Donnell, Ph.D. Carl R. Sullivan, M.D. William Petros, Pharm.D. Department of Basic Pharmaceutical Sciences Morgantown, West Virginia 2013 Keywords: Sigma receptor, Ketamine, Methamphetamine, Depression, Neurotoxicity ABSTRACT The Involvement of Sigma Receptor Modulation in the Antidepressant-Like Effects of Ketamine Matthew J. Robson Depression is estimated to affect at least 30% of the world’s population at some point during their lives. Currently marketed antidepressants require a period of at least 2 to 3 weeks to display any antidepressant effects in clinical populations and rates of clinical resistance to the antidepressant effects of these drugs are high. Ketamine is an N-methyl-D-aspartate (NMDA) antagonist and dissociative anesthetic that has been shown to display rapid acting and prolonged antidepressant activity in small- scale human clinical trials. Ketamine also binds to sigma receptors, which are believed to be protein targets for a potential new class of antidepressant medications. The purpose of this study was to determine the involvement of sigma receptors in the antidepressant-like actions of ketamine. Competition binding assays were performed to assess the affinity of ketamine for sigma-1 and sigma-2 receptors. The antidepressant-like effects of ketamine were assessed in vitro using a neurite outgrowth model and PC12 cells, and in vivo using the forced swim test. The sigma receptor antagonists, 4- methoxy-3-(2-phenylethoxy)-N,N-dipropylbenzeneethanamine hydrochloride (NE-100) and N-[2-(3,4- dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide (BD1047), were evaluated in conjunction with ketamine in these assays to determine the involvement of sigma receptors in the antidepressant-like effects of ketamine. Ketamine bound to both sigma-1 and sigma-2 receptors with µM affinities. Additionally, ketamine potentiated nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells and this effect was attenuated in the presence of NE-100. Ketamine also displayed antidepressant-like effects in the forced swim test; however, these effects were not attenuated by pretreatment with NE-100 or BD1047. Taken together, these data suggest that sigma receptor-mediated neuronal remodeling may contribute to the antidepressant effects of ketamine. DEDICATION This dissertation is dedicated to The most supportive, loving parents imaginable James E. and Katherine S. Robson The memory of my late grandmother, Katherine Robson, who taught me life lessons I shall never forget… And my loving wife and best friend Catherine E. Robson iii ACKNOWLEDGEMENTS I would like to first acknowledge the support and mentorship I received from, Dr. Rae R. Matsumoto. Without her guidance, encouragement, support and mentorship none of what is included in the current dissertation would have been possible. She has been a constant source of inspiration and motivation to pursue many of the opportunities presented to me within the last four years. Her guidance has allowed me to expand not only as a scientist, but as an individual as well. My sincerest gratitude goes out to her for all of the opportunities and memories during my time at West Virginia University. Secondly, I wish to thank the remainder of my committee members, Jason Huber, Ph.D., James O’Donnell, Ph.D., Carl Sullivan, M.D. and William Petros, Pharm. D. for valuable insight into many of the projects contained within this dissertation. I would especially like to thank Jason Huber, Ph.D. for the collaborative experiences with members of his lab on several projects in the current dissertation. Without these collaborations, much of this work would not have been possible. I would like to also thank our medicinal chemist collaborators, Christopher McCurdy, Ph.D. at the University of Mississippi and Andrew Coop, Ph.D. at the University of Maryland for synthesizing many of the compounds utilized in these studies. I would also like to thank members of the Matsumoto lab, both past and present. Michael Seminerio, Ph.D., Meenal Elliott, Ph.D., Jason Healy, Yantong Xu, Ph.D., Jamaluddin Shaikh, Ph.D., James Fishback, Ph.D., Nidhi Kaushal, Ph.D., Bahar Noorbakhsh, and Christina Byrne-Hoffman. I would also like to thank members of the Huber lab, including Ryan Turner, Zachary Naser and Aric Logsdon. Lastly, I would like to say thank you to my parents, James and Katherine, my sister, Melissa, and my wife, Catherine, for all the years of love, support and guidance that has helped me achieve many of my goals in life thus far. iv TABLE OF CONTENTS ABSTRACT LIST OF FIGURES LIST OF TABLES ABBREVIATIONS CHAPTER 1. Introduction: Ketamine, Depression and Sigma Receptors …………………………...................... 1 1.1. Depression ……………………………………………………………………………………………………………………………………. 2 1.2. Currently Utilized Treatments for Depression ………………………………………………………………………………. 2 1.3. Sigma Receptors …………………………………………………………………………………………………………………………… 3 1.3.1. Sigma-1 Receptors ………………………………………………………………………………………………………... 4 1.3.2. Sigma-2 Receptors ……………………………………………………………………………………………………….. 5 1.4. Sigma Receptors and Depression …………………………………………………………………………………………………. 5 1.5. Sigma Receptors and Glutamatergic Signaling ................................................................................ 9 1.6. Ketamine and Depression ……………………………………………………………………………………………………………. 10 1.7. Ketamine and Sigma Receptors ……………………………………………………………………………………………………. 11 CHAPTER 2. Evaluation of Sigma Receptors in the Antidepressant-Like Effects of Ketamine In Vitro and In Vivo ……………………………………………………………………………………………………………………………... 13 2.1. Introduction …………………………………………………………………………………………………………………………………. 14 2.2. Materials and Methods ………………………………………………………………………………………………………………… 16 2.3. Results ………………………………………………………………………………………………………………………………………….. 20 2.4. Discussion …………………………………………………………………………………………………………………………………….. 28 2.5. Contributions ……………………………………………………………………………………………………………………………….. 33 v ABSTRACT …………………………………………………………………………………………………………………………………………. 34 CHAPTER 3. Methamphetamine Abuse and Neurotoxicity……………………………………………………….………. 35 3.1. Drug Abuse ……………………………………………………………………………………………………………………………….. 36 3.2. Sigma Receptors and Drug Abuse ……………………………………………………………………………………………… 36 3.3. Methamphetamine (METH) ………………………………………………………………………………………………………. 37 3.4. METH-Induced Neurotoxicity: Potential Mechanisms ………………………………………………………………. 39 3.5. Sigma Receptors and METH ………………………………………………………………………………………………………. 42 3.6. Sigma Receptor Ligands as Potential Treatments for the Negative Side Effects of METH…………… 44 CHAPTER 4. Sigma Receptor Antagonist Attenuation of METH-Induced Neurotoxicity is Correlated to Body Temperature Modulation………………………………………………………………………………………………………… 50 4.1. Introduction ………………………………………………………………………………………………………………………………. 51 4.2. Materials and Methods ……………………………………………………………………………………………………………… 52 4.3. Results ……………………………………………………………………………………………………………………………………….. 54 4.4. Discussion ………………………………………………………………………………………………………………………………….. 58 4.5. Contributions ……………………………………………………………………………………………………………………………… 62 CHAPTER 5. AC927 Pretreatment Mitigates METH-Induced Changes in Striatal Gene Expression ……. 63 5.1.Introduction ………………………………………………………………………………………………………………………………… 64 5.2. Materials and Methods ………………………………………………………………………………………………………………. 64 5.3. Results ………………………………………………………………………………………………………………………………………… 67 5.4. Discussion …………………………………………………………………………………………………………………………………… 74 vi 5.5. Contributions ……………………………………………………………………………………………………………………………… 75 CHAPTER 6. METH Causes PERK-Mediated Endoplasmic Reticulum Stress in NG108-15 Cells Through a Mechanism Independent of Sigma Receptors…………………………………………………………………………………… 77 6.1. Introduction …………………………………………………………………………………………………………………………....... 78 6.2. Materials
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