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Liquid Chromatography-Mass Spectrometry Strategies for in Vivo Neurochemical Monitoring with Microdialysis

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Liquid Chromatography-Mass Spectrometry Strategies for in Vivo Neurochemical Monitoring with Microdialysis Liquid Chromatography-Mass Spectrometry Strategies for in vivo Neurochemical Monitoring with Microdialysis by Jenny-Marie T. Wong A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Chemistry) in the University of Michigan 2016 Doctoral Committee: Professor Robert T. Kennedy, Chair Professor Kristina I. Håkansson Professor Mark E. Meyerhoff Professor Martin G. Myers Jr. © Jenny-Marie T. Wong All Rights Reserved 2016 DEDICATION To my friends and family who have always supported me. ii ACKNOWLEDGEMENTS I thank Professor Robert T. Kennedy for accepting me into his group, and challenging me to think deeper and to achieve more. His support and encouragement during my time at the University of Michigan means so much. I also extend my gratitude to my dissertation committee members, Professor Kristina Håkansson, Professor Mark Meyerhoff, and Professor Martin G. Myers Jr., whose insight, thoughtful questions, and advice has helped shape my research, given me a broader perspective, and deepened my understanding. I extend special thanks to my previous mentors Professor Joseph A. Gardella, Dr. AnneMarie Block, Dr. Susan Leong, and Mrs. Anne Ruppert, who continue to mentor me, and encouraged me to pursue chemistry with research opportunities early in my academic career. Your support and encouragement has made this journey possible. I also thank my colleagues Dr. Omar Mabrouk, Dr. Neil Hershey, Dr. Peng Song, Dr. Thomas Slaney, Dr. Jing Nie, Dr. Shuwen Sun, Dr. Ying Zhou, Dr. Kennon Deal, Dr. Shi Jin, Dr. Erik Guetschow, Doc Colladeen Dugan, Dr. Jim Grinias, Dr. Katy Nesbitt, Paige Malec, Non Ngernsutivorakul, Alec Valenta, Daniel Steyer, Claire Ouimet, Dr. Kirsten Porter-Stransky, Dr. Ream Al-Hassani, Dr. Jordan McCall, Dr. Christa Patterson- Polidori, Dr. Jeffery Pettibone, and Dr. Sarah Mikelman. I have learned so much from each of you, and have valued your patience, willingness to lend a hand, and friendship. A iii special thanks to Dr. Omar Mabrouk and Dr. Neil Hershey for my initial training, Dr. Ying Zhou for guidance on neuropeptides, and Dr. Jim Grinias for teaching me fundamental chromatography and being a great friend in and out of lab. To my friends I made here, who have supported me throughout graduate school: Julia Bourg, Qi Zhang, Betsy Brown, and Sarah Mikelman. You have been my support and my role models. You were there when the stress felt like too much, and always reminded me that I could do it. Without your friendship, graduate school would have been impossible, boring, and less fun. To my family, especially my dad, Tai-Gue, and Tai-Gue Cheung. Without the unconditional love and support you have provided me throughout my life, I am certain I would not have made it to where I am today. You stood by me in the worst times, consoled me, and reminded me that life is both yin and yang. Even in my darkest times, I knew I was always loved. I could always count on you to make me laugh, smile, and remind me that there are silver linings in every situation. And finally to Sam. You have always seen the best in me, believed in me, and made me a better person. You have been my rock, keeping me sane through this journey, my partner in adventure, my better half, and my on-call editor. Your love and support through these last few years mean more to me than words can say. I have loved the adventures we have shared, and look forward to the future adventures that lie ahead. iv TABLE OF CONTENTS DEDICATION .................................................................................................................... ii ACKNOWLEDGEMENTS ............................................................................................... iii LIST OF FIGURES .......................................................................................................... vii LIST OF TABLES ............................................................................................................ xv LIST OF APPENDICES ................................................................................................. xvii LIST OF ABBREVIATIONS ........................................................................................ xviii ABSTRACT ..................................................................................................................... xxi CHAPTER 1: INTRODUCTION ....................................................................................... 1 Detection of small molecules in dialysate ...................................................................... 6 Detection of neuropeptides in dialysate ........................................................................ 12 Applications of LC-MS for dialysate analysis: Neurochemical monitoring during selective neuronal stimulation ....................................................................................... 22 Dissertation overview ................................................................................................... 25 CHAPTER 2: BENZOYL CHLORIDE DERIVATIAZATION WITH LIQUID CHROMATOGRAPHY MASS SPECTROMETRY FOR TARGETED METABOLOMICS OF NEUROCHEMICALS IN BIOLOGICAL SAMPLES ............. 27 Introduction ................................................................................................................... 27 Experimental ................................................................................................................. 34 Results and Discussion ................................................................................................. 41 Conclusions ................................................................................................................... 66 CHAPTER 3: VENTRAL TEGMENTAL AREA NEUROTENSIN SIGNALING LINKS THE LATERAL HYPOTHALAMUS TO LOCOMOTOR ACTIVITY AND STRIATAL DOPAMINE EFFLUX IN MALE MICE ......................................................................... 67 Introduction ................................................................................................................... 67 Materials and Methods .................................................................................................. 69 v Results ........................................................................................................................... 76 Discussion ..................................................................................................................... 86 CHAPTER 4: SIMULTANEOUS IN VIVO MICRODIALYSIS AND LOCAL OPTOGENETIC STIMULATION TO MEASURE OPIOID PEPTIDE RELEASE IN DYNORPHIN CONTAINING CELLS IN MOUSE NUCLEUS ACCUMBENS SHELL ........................................................................................................................................... 89 Introduction ................................................................................................................... 89 Methods......................................................................................................................... 91 Results and Discussion ................................................................................................. 98 Conclusions ................................................................................................................. 115 CHAPTER 5: IN VIVO QUANTIFICATION OF STRIATAL OPIOID PEPTIDES FOLLOWING 6-HYDROXYDOPAMINE LESIONS .................................................. 116 Introduction ................................................................................................................. 116 Methods....................................................................................................................... 121 Results and Discussion ............................................................................................... 124 Conclusions ................................................................................................................. 131 CHAPTER 6: A POTENTIAL OXYTOCIN TREATMENT FOR L-DOPA INDUCED DISKINESIAS ................................................................................................................ 133 Introduction ................................................................................................................. 133 Methods....................................................................................................................... 136 Results and Discussion ............................................................................................... 139 Conclusions ................................................................................................................. 145 CHAPTER 7: FUTURE DIRECTIONS ......................................................................... 146 APPENDIX A: Preparation of Benzoyl Chloride Standards and Internal Standards ..... 159 APPENDIX B: Microdialysis Probe Fabrication ........................................................... 166 REFERENCES ............................................................................................................... 181 vi LIST OF FIGURES Figure 1-1 Microdialysis probes utilize inlet and outlet capillaries ensheathed by a semi- permeable membrane allowing for sampling of surrounding tissue. Compounds below the MWCO (blue spheres) of the membrane diffuse in and out of the probe based on concentration gradients. The semi-permeable membrane excludes large molecules (purple octagons) such as proteins and enzymes. ...................................... 2 Figure 1-2 Reaction scheme of benzoyl
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