Graduate Theses, Dissertations, and Problem Reports 2015 Evaluation of the antidepressant potential of dextromethorphan Linda Nguyen Follow this and additional works at: https://researchrepository.wvu.edu/etd Recommended Citation Nguyen, Linda, "Evaluation of the antidepressant potential of dextromethorphan" (2015). Graduate Theses, Dissertations, and Problem Reports. 6309. https://researchrepository.wvu.edu/etd/6309 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]. Evaluation of the antidepressant potential of dextromethorphan Linda Nguyen 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 Pharmacological and Pharmaceutical Sciences Han-Ting Zhang, M.D./Ph.D., Chair Rae R. Matsumoto, Ph.D. David P. Siderovski, Ph.D. Paola Pergami, M.D./Ph.D. Patrick J. Marshalek, M.D. Department of Behavioral Medicine and Psychiatry Morgantown, West Virginia 2015 Keywords: dextromethorphan, ketamine, imipramine, dextrorphan, depression, antidepressant, sigma-1 receptors, AMPA receptors, BDNF, NGF © 2015 Linda Nguyen ABSTRACT Evaluation of the antidepressant potential of dextromethorphan Linda Nguyen Depression affects more than 350 million people and is the leading cause of disability worldwide. Major challenges in the management of depression remain the 4-12 weeks of delayed efficacy and 30% of patients who are resistant to the therapeutic effects of current pharmaceutical treatments. We herein examined whether dextromethorphan (DM) may be able to take on these challenges, because 1) it has overlapping pharmacology with ketamine, which has shown rapid (within 24 hours) antidepressant effects, even in treatment-resistant individuals; 2) unlike ketamine with its notable abuse liability and adverse effects, DM is an over-the-counter antitussive with a high safety margin; and 3) DM binds to several protein targets which are similar to conventional medications as well as distinctive from them, affording possibilities of efficacy in treatment-refractory depression (TRD). The antidepressant-like effects of DM were determined in mice in the forced swim test (FST) and tail suspension test (TST), the two most validated animal models for predicting antidepressant actions. Next, the role of sigma-1 and AMPA receptors in the antidepressant-like effects of DM was examined because mounting evidence suggests that these novel mechanisms contribute to a faster onset of antidepressant efficacy. We also assessed in vivo and in vitro whether DM can promote neural adaptations, which is thought to be a final common pathway for fast acting and conventional antidepressants. Finally, since DM undergoes substantial first-pass metabolism to active metabolites, we evaluated the impact of metabolism on the antidepressant-like effects of DM to determine whether the DM effects are likely mediated through itself or its major metabolites. Our results revealed that DM produces antidepressant-like actions in both the FST and TST, similar to the fast acting and conventional antidepressant controls represented by ketamine and imipramine. Whereas the antidepressant-like effects of DM were blocked by pretreatment with a sigma-1 receptor antagonist (BD1063) or AMPA receptor antagonist (NBQX), the antidepressant-like effects of ketamine were blocked with only NBQX; neither antagonists attenuated the antidepressant-like effects of imipramine. This indicates while only AMPA receptors may play a significant role in mediating the antidepressant-like behaviors of ketamine, both AMPA and sigma-1 receptors may have pivotal roles for DM. Moreover, ketamine rapidly increased hippocampal pro-BDNF levels (within 40 minutes), whereas DM and imipramine did not alter pro-BDNF or BDNF levels in mouse hippocampus or frontal cortex, two key brain regions implicated in depression, in the same time frame. In an in vitro model of neurite growth, however, all three drugs potentiated NGF-induced neurite outgrowth, suggesting DM may work through other trophic factors (e.g., NGF) to facilitate antidepressant-relevant neural adaptations. Lastly, slowing down the metabolism of DM potentiated its antidepressant-like effects, indicating DM rather than its metabolites is the primary mediator of the antidepressant-like effects observed herein. Overall, our results indicate DM produces antidepressant-like effects through mechanisms that overlap in part with ketamine. Taken together with a recent clinical report of DM’s efficacy (some within 1-2 days) for treatment-resistant bipolar depression, these data suggest DM may not only elicit antidepressant effects faster than the currently approved medications, but also have efficacy in TRD. ACKNOWLEDGEMENTS This dissertation could not have been completed without the great support that I have received from many people over the “long” and arduous two years. First and foremost, I would like to express my deep and sincere gratitude to my advisor, Dr. Rae R. Matsumoto. Without her encouragement and mentorship, none of what is included in the current dissertation would have been possible, nor would I have been able to complete the work in such a short amount of time. Dr. Matsumoto has been a constant source of inspiration and motivation to pursue many of the opportunities presented to me as a graduate student. Even before I officially started my graduate training in her lab, she had encouraged me to write my very first, first-author original research paper. In addition, her guidance and advice on matters that extend beyond the benchtop has allowed me to grow not only as a scientist, but also as an individual. Secondly, I wish to thank the remainder of my committee members, Dr. Han-Ting Zhang, Dr. Paola Pergami, Dr. David P. Siderovski, and Dr. Patrick J. Marshalek for their support, guidance, and helpful suggestions. I would especially like to thank Dr. Siderovski, for being my go-to-person currently at WVU when in need; Dr. Zhang, for giving me a new lab home; and Dr. Marshalek for partaking in the journey with me to translate my preclinical findings into a clinical study (or at least try to) at WVU. I would also like to thank past members of the Matsumoto lab: Jason Healy, Ying Zhang, and especially Matthew Robson, for training me in my very first mouse depression study, and Anna Scandinaro, for holding down the Matsumoto lab fort with me while it lasted. Special thanks to Brandon Lucke-Wold, for his collaborative spirit as we trekked through the graduate training of the M.D./Ph.D. program together; and Dr. Jeffrey Wimsatt, for believing in my abilities to get to the “heart” of the matter (or at least the mouse) and allowing me take part in several mouse pharmacokinetic studies. Lastly, I would like to say thank you to my family for all the years of unconditional love and never-ceasing support, and my friends for helping me maintain some social balance in my life. iii DEDICATION This dissertation is dedicated to my loving parents, whose own perseverance and hard work inspires me to pursue my own dreams with great gratitude and passion. iv TABLE OF CONTENTS ABSTRACT ACKNOWLEDGEMENTS DEDICATION TABLE OF CONTENTS LIST OF FIGURES LIST OF TABLES LIST OF ABBREVIATIONS CHAPTER 1: Introduction ............................................................................................................1 1.1. Depression ...............................................................................................................................2 1.2. Available treatments for depression and their limitations ........................................................3 1.3. The promise and perils of ketamine .........................................................................................7 1.4. Ketamine: where do we go from here? ....................................................................................9 1.5. Dextromethorphan (DM) as a logical next step .......................................................................10 CHAPTER 2: DM as a potential safe and effective antidepressant ............................................12 2.1. History of DM .........................................................................................................................13 2.2. Pharmacokinetics and metabolism ...........................................................................................14 2.3. Pharmacodynamics profile .......................................................................................................14 2.4. Proposed mechanisms of antidepressant action .......................................................................16 2.4.1. Monoaminergic system .........................................................................................................17 2.4.2. Sigma-1 receptors..................................................................................................................22