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Using a Novel Optogenetic Approach to Directly Assess 5-Ht1a Wayne State University Wayne State University Dissertations 1-1-2015 Using A Novel Optogenetic Approach To Directly Assess 5-Ht1a Somatodendritic Autoreceptor Function In Response To Chronic Selective Serotonin Reuptake Inhibitor Treatment Kelly Marie Mcgregor Wayne State University, Follow this and additional works at: http://digitalcommons.wayne.edu/oa_dissertations Part of the Neurosciences Commons, Pharmacology Commons, and the Psychiatric and Mental Health Commons Recommended Citation Mcgregor, Kelly Marie, "Using A Novel Optogenetic Approach To Directly Assess 5-Ht1a Somatodendritic Autoreceptor Function In Response To Chronic Selective Serotonin Reuptake Inhibitor Treatment" (2015). Wayne State University Dissertations. Paper 1316. This Open Access Dissertation is brought to you for free and open access by DigitalCommons@WayneState. It has been accepted for inclusion in Wayne State University Dissertations by an authorized administrator of DigitalCommons@WayneState. USING A NOVEL OPTOGENETIC APPROACH TO DIRECTLY ASSESS 5-HT1A SOMATODENDRITIC AUTORECEPTOR FUNCTION IN RESPONSE TO CHRONIC SELECTIVE SEROTONIN REUPTAKE INHIBITOR TREATMENT by KELLY MARIE MCGREGOR DISSERTATION Submitted to the Graduate School of Wayne State University, Detroit, Michigan in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY 2015 MAJOR: PHARMACOLOGY (Molecular Neuropharmacology) Approved By: ________________________________________ Advisor Date ________________________________________ ________________________________________ ________________________________________ ________________________________________ ________________________________________ DEDICATION I would like to dedicate this work to all those individuals who are affected, directly or indirectly, by depression and/or any other mental disorder. I truly hope that adequate treatment will soon be available. ii ACKNOWLEDGMENTS There are many people that deserve credit for my success in graduate school. First and foremost, I would like to thank my mentor, Dr. Rodrigo Andrade, for his guidance and support over the past four years. I would also like to thank each of my committee members: Dr. Karen List, Dr. Paul Walker, Dr. Gregory Kapatos, Dr. Michael Bannon and Dr. Sokol Todi. I am grateful for your thoughts and input into my project, and for your dedication to my success. I would also like to acknowledge my previous mentor, Dr. Keith Lookingland, for believing in me and always putting a smile on my face. And to Dr. Stanley Terlecky, for his continued enthusiasm and kindness. I would like to thank the current and previous members of the Andrade lab, especially Peter Tanaka, Alicia Aleardi, Daniel Huereca, and our ‘lab mom’, Elaine Andrade. Of course, I could not have gotten to this point if it were not for God, my friends and family. Katie, Alicia, Asra, Janelle, Rachel- thanks for letting me vent. Mom and Dad- thanks for teaching me what matters most in life. I will forever be grateful for your long pep talks, encouragement, prayers, and unconditional love. I would also like to thank my twin, Dr. Stacey, who has always kept me going (likely through unspoken competition), my sisters Meghan and Maria, and my little brother Doug. Derrick- thanks for always being there for me. I also need to acknowledge my Grandma Wetli, who has been an absolutely immaculate role model. I miss you. Of course, a special thanks must be made to Sister Connie Gleason, Dr. Stephen and Grozda Swetech, and to my Baba for their encouragement and acceptance. Finally, Dr. Jon Swetech- I am forever grateful for your unfaltering support, love and craziness, and for getting me Toby so I could finish graduate school. Last but not least, I would also like to thank the PhRMA Foundation for financially supporting my research through a Pharmacology/Toxicology pre-doctoral fellowship award, and for the National Institutes of Health grant R01MH043985 (awarded to Dr. Rodrigo Andrade). iii TABLE OF CONTENTS Dedication ………………………………………………………………………………………………... ii Acknowledgements …………………………………………………………………………………….. iii List of Figures …………………………………………………………………………………………..... v Chapter 1 Introduction ……………………………………………………………………………………1 Depression and Antidepressants …………………………………………………...………….1 History of Antidepressant Treatments- TCAs and MAOIs ……………………………………1 Search for the Mechanism of Action of Antidepressants ………………………………..…. 4 Development of SSRIs ……………………………………………………………………..….. 5 Serotonin Hypothesis of Depression …………………………………………………………. 6 Involvement of the Serotonin System in the Therapeutic Effects of Antidepressants …... 7 Mechanism of Action of Antidepressants, Revisited ………………………………….…..... 8 Autoreceptor Desensitization Hypothesis ………………………………………………...….. 9 Goal of the Current Work …………………………………………………………………..…. 11 Chapter 2 Results ………………………………………………………………………………..…….. 13 Use of Optogenetics to Selectively Evoke 5-HT1A Autoreceptor-mediated Autoinhibition ……………………………………………………………………………………………………13 Effects of Chronic Fluoxetine on Autoreceptor-mediated Currents ……………………… 19 5-HT Dose Response Analysis ………………………………………………………………. 22 Effects of Acute Fluoxetine …………………………………………………………………... 24 Effects of Subchronic Fluoxetine Administration …………………………………………… 26 Chapter 3 Discussion ……………………………………………………………………………..…… 29 Benefits of Optogenetics for Assessment of Autoinhibition ………………………..……… 29 Major Findings …………………………………………………………..…………………….. 32 Potential Limitations of the Current Approach ………………………………..……………. 33 Previous Reports that Cast Doubt on the Autoreceptor Desensitization Hypothesis ….. 35 iv Previous Reports that Chronic Fluoxetine Treatment Caused 5-HT1A Autoreceptor Desensitization ………………………………………………………………………...…….... 35 Previous Reports of the Effects of Acute and Subchronic Fluoxetine on the 5-HT1A Autoreceptor-mediated Signal ……………………………………………………………….. 37 Potential Factors Contributing to the Alterations in 5-HT1AR Ilight …………………………. 39 Possible Future Antidepressant Treatments ………………………………………..…...… 41 Concluding Remarks …………………………………………………………………………. 43 Materials and Methods ………………………….…………………………………………………….. 44 References …………………………………………………………………………………………...… 50 Abstract ……………………………………………………………………………………………….… 63 Autobiographical Statement ………………………………………………………………………..… 65 v LIST OF FIGURES Figure 1: Effects of SSRI administration on the activity of 5-HT neurons in the DRN according to the autoreceptor desensitization theory …………………………………………………………...… 11 Figure 2: Genetically modified mice models for the selective targeting of the light-gated ion channel, ChR, to serotonergic neurons in our preparation ………………………………………… 15 Figure 3: Use of the SERT promoter to target Cre recombinase to 5-HT neurons in brainstem slices ……………………………………………………………………………………………………. 16 Figure 4: Characterization of ChR in 5-HT cells of SERT-Cre X Ai32, Pet1-Cre X Ai32 and TpH2- ChR mice models ………………..…….…………………………………………………………….....17 Figure 5: Genetically modified SERT-Cre X Ai32 mice permit optical stimulation-mediated control over the phenomenon of autoinhibition ……………………………………………………….……... 18 Figure 6: The 5-HT1AR Ilight response characteristics of 5-HT neurons from non-treated and sham treated SERT-Cre X Ai32 mice were not significantly different from one another ………………………………………………………………………………………….………………... 20 Figure 7: Chronic fluoxetine treatment induces alterations in the 5-HT1A autoreceptor-mediated response ………………………………………………………………………………………………... 21 Figure 8: 5-HT concentration response curves conducted in the presence of bath fluoxetine (1 µM) do not indicate a change in 5-HT1A autoreceptor sensitivity following chronic fluoxetine treatment ……………………………………………………………………………………………….. 23 Figure 9: Bath application of fluoxetine (1 µM) produces 5-HT1AR Ilight characteristics in control cells that are similar to those of chronic fluoxetine treatment ……………………………………… 25 Figure 10: Effects of subchronic fluoxetine treatment on the 5-HT1A autoreceptor-mediated signal ………………………………………………………………………………….………………………... 28 vi 1 CHAPTER 1 INTRODUCTION Depression and Antidepressants Depression is a serious medical illness that is characterized by deep, persistent feelings of sadness, worthlessness and general loss of interest and pleasure in everyday activities (anhedonia). It manifests itself throughout many aspects of life, often causing sleep disturbances, concentration deficits, chronic fatigue, and changes in appetite and weight. Depression is also a very common condition, affecting approximately 8% of teenagers and adults in the United States (Pratt and Brody, 2014). It also represents a substantial financial burden. According to Greenberg et al. (2003), this illness cost the United States an estimated 83.1 billion dollars in 2000, which is a significant increase from the 43.7 billion estimated to have been spent in 1990. Unfortunately, depression is often accompanied by suicidal ideation, making suicide the 10th leading cause of death in the United States in 2013 (Kochanek et al., 2014). Fortunately, there are a number of effective antidepressant medications. Whereas the increasing prevalence of depression remains a matter of debate, the ever enhancing popularity of antidepressants is undeniable. According to the National Center for Health (2014), these medications are used by an estimated 11% of American adults, which is more than a four-fold increase from 1988-1994 to 2007-2010. Antidepressants are the third most common class of prescription drug used by adolescents (12-19 years of age) and the most common class
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