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FSU ETD Template Florida State University Libraries Electronic Theses, Treatises and Dissertations The Graduate School 2018 Sex Differences in the Effects of Low- Dose Ketamine in Rats: A Behavioral, Pharmacokinetic and Pharmacodynamic Analysis Samantha K. Saland Follow this and additional works at the DigiNole: FSU's Digital Repository. For more information, please contact [email protected] FLORIDA STATE UNIVERSITY COLLEGE OF MEDICINE SEX DIFFERENCES IN THE EFFECTS OF LOW-DOSE KETAMINE IN RATS: A BEHAVIORAL, PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS By SAMANTHA K. SALAND A Dissertation submitted to the Department of Biomedical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy 2018 Samantha Saland defended this dissertation on April 18, 2018. The members of the supervisory committee were: Mohamed Kabbaj Professor Directing Dissertation Thomas Keller University Representative James Olcese Committee Member Branko Stefanovic Committee Member Zuoxin Wang Committee Member The Graduate School has verified and approved the above-named committee members, and certifies that the dissertation has been approved in accordance with university requirements. ii I dedicate this work to my loving husband and to my parents—without their endless encouragement and unconditional support throughout the years, this would not have been possible. iii ACKNOWLEDGEMENTS I would like to acknowledge all those in the Department of Biomedical Sciences here at Florida State University who have made it possible for me to succeed, not only through financial and research support, but by providing an environment of opportunity, understanding and encouragement time and again during my time in the graduate program. I would also like to express my gratitude to my committee members for their continued guidance and support throughout all these years—thank you for challenging me and expanding my continuous search for knowledge. Most importantly, I am sincerely thankful to my advisor, Dr. Mohamed Kabbaj, whose mentorship has been transformative to my life as a scientist and as a person. I owe my continued pursuit of science and growth as a researcher to his unwavering guidance and support throughout the great moments, and most notably, the difficult ones. Thank you for teaching me the value of perseverance, and for fostering a setting in which asking challenging questions and thinking creatively are both encouraged and valued. Your mentorship has been invaluable. iv TABLE OF CONTENTS List of Tables ................................................................................................................................. vii List of Figures ................................................................................................................................viii Abstract ........................................................................................................................................... ix 1. INTRODUCTION.......................................................................................................................1 1.1 Primer on Ketamine and Sex Differences in Depression.....................................................1 1.2 Current state of knowledge on sex differences in effects of low-dose ketamine.................2 1.2.1 Effects of ketamine under baseline conditions..........................................................2 1.2.2 Effects of ketamine under conditions of stress..........................................................3 1.2.2.1 Sex differences in response to chronic stress ...............................................3 1.2.2.2 Sex differences in antidepressant response following chronic stress ..........4 1.3 Pharmacokinetic considerations and relevance to clinical populations ...............................6 1.3.1 Preclinical sex differences in ketamine pharmacokinetics........................................7 1.3.2 Clinical sex differences in ketamine pharmacokinetics ............................................7 1.3.3 Possible explanations for sex- and species-specific pharmacokinetic differences ...8 1.4 Dissertation Plan ..................................................................................................................9 2. HEDONIC SENSITIVITY TO LOW-DOSE KETAMINE IS MODULATED BY GONADAL HORMONES IN A SEX-DEPENDENT MANNER ...........................................10 2.1 Introduction ........................................................................................................................10 2.2 Materials and Methods.......................................................................................................12 2.2.1 Animals ...................................................................................................................12 2.2.2 Ovariectomy/Gonadectomy ....................................................................................12 2.2.3 Cyclic hormone treatment regimen and testosterone supplementation...................13 2.2.4 Estrous cycle monitoring.........................................................................................13 2.2.5 Continuous-access sucrose preference test .............................................................13 2.2.6 Experimental design ................................................................................................14 2.2.6.1 Experiment 1a: Effect of cyclic E2 and P4 treatment on hedonic response to low-dose ketamine in ovariectomized female rats.................................14 2.2.6.2 Experiment 1b: Effect of low-dose ketamine on hedonic behavior following cyclic E2 and P4 treatment in intact male rats ..........................14 2.2.6.3 Experiment 2a: Effect of chronic testosterone treatment on hedonic response to low-dose ketamine in intact female rats..................................15 2.2.6.4 Experiment 2b: Effect of low-dose ketamine on hedonic behavior following gonadectomy and testosterone supplementation in male rats ...15 2.2.7 Western blotting ......................................................................................................16 2.2.8 Statistical analysis ...................................................................................................16 2.3 Results ................................................................................................................................18 2.3.1 Influence of cyclic E2 and P4 treatment on hedonic response to low-dose ketamine in ovariectomized female rats .................................................................................18 v 2.3.2 Effect of low-dose ketamine on hedonic behavior following cyclic E2 and P4 treatment in intact male rats ....................................................................................18 2.3.3 Effect of chronic testosterone treatment on hedonic response to low-dose ketamine in intact female rats .................................................................................................22 2.3.4 Effect of low-dose ketamine on hedonic behavior following gonadectomy and testosterone supplementation in male rats...............................................................23 2.3.5 Integrated analysis of ketamine’s effects across sex and hormonal status: Z-score normalization of sucrose preference .......................................................................25 2.3.6 Effect of cyclic E2 and P4 treatment on hippocampal BDNF protein levels and downstream signaling effectors in female and male rats ........................................27 2.4 Discussion ..........................................................................................................................30 3. SEX DIFFERENCES IN THE PHARMACOKINETICS OF LOW-DOSE KETAMINE IN PLASMA AND BRAIN OF MALE AND FEMALE RATS ...................................................39 3.1 Introduction ........................................................................................................................39 3.2 Materials and Methods.......................................................................................................41 3.2.1 Animals ...................................................................................................................41 3.2.2 Estrous cycle monitoring.........................................................................................41 3.2.3 Pharmacokinetics experimental procedures ............................................................42 3.2.3.1 Ketamine treatment and sample collection ................................................42 3.2.3.2 Sample preparation.....................................................................................42 3.2.4 Quantification of ketamine and metabolites in biological matrices ........................44 3.2.4.1 HPLC for plasma samples..........................................................................44 3.2.4.2 HPLC for brain tissue samples...................................................................44 3.2.4.3 Mass spectrometry......................................................................................44 3.2.5 Pharmacokinetics data analysis ...............................................................................45 3.2.6 Statistical analysis ...................................................................................................47 3.3 Results ................................................................................................................................47 3.3.1 Plasma concentrations of ketamine
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