East Tennessee State University Digital Commons @ East Tennessee State University Electronic Theses and Dissertations Student Works 8-2015 An Analysis of the Interaction of Methylphenidate and Nicotine in Adolescent Rats: Effects on BDNF Elizabeth D. Freeman East Tennessee State University Follow this and additional works at: https://dc.etsu.edu/etd Part of the Behavioral Neurobiology Commons, Laboratory and Basic Science Research Commons, Other Animal Sciences Commons, Pharmacology Commons, and the Psychology Commons Recommended Citation Freeman, Elizabeth D., "An Analysis of the Interaction of Methylphenidate and Nicotine in Adolescent Rats: Effects on BDNF" (2015). Electronic Theses and Dissertations. Paper 2572. https://dc.etsu.edu/etd/2572 This Dissertation - Open Access is brought to you for free and open access by the Student Works at Digital Commons @ East Tennessee State University. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of Digital Commons @ East Tennessee State University. For more information, please contact [email protected]. An Analysis of the Interaction of Methylphenidate and Nicotine in Adolescent Rats: Effects on BDNF _____________________ A dissertation presented to the faculty of the Department of Psychology East Tennessee State University In partial fulfillment of the requirements for the degree Doctor of Philosophy in Psychology _____________________ by Elizabeth D. Freeman August 2015 _____________________ Russell W. Brown, PhD, Chair Eric W. Sellers, PhD Matthew I. Palmatier, PhD Jon R. Webb, PhD Rich M. Kostrzewa, PhD Keywords: Methylphenidate, Ritalin, Nicotine, Sensitization, Conditioned Place Preference, BDNF, Adolescence ABSTRACT An Analysis of the Interaction of Methylphenidate and Nicotine in Adolescent Rats: Effects on BDNF by Elizabeth D. Freeman This investigation was an analysis of the interaction of adolescent exposure to methylphenidate (MPH; trade name: Ritalin) on nicotine sensitization and conditioned place preference (CPP) in a rodent model and underlying mechanisms of this effect. Animals were treated IP with 1 mg/kg MPH or saline using a ―school day‖ regimen of five days on, two days off, from postnatal day (P) 28-50. During the final two weeks of MPH treatment, animals were either behaviorally sensitized to nicotine (0.5 mg/kg free base) or saline for 10 days, or conditioned to nicotine or saline using the CPP behavioral paradigm. In addition, three days after behavioral sensitization was complete, animals were analyzed for stress behavior using the forced swim stress behavioral test. In addition, 24 hours after post-test conditioning animals were analyzed for the effect of a clinically relevant dose of pre-exposed MPH (1 mg/kg) and nicotine treatment on the expression of BDNF in the nucleus accumbens and dorsal hippocampus. Behavioral results revealed that adolescent pre-exposure to MPH blunted nicotine behavioral sensitization in both male and female rats during the first week of testing. However, MPH enhanced nicotine CPP in both adolescent male and female rats. Interesting, animals administered MPH demonstrated a significantly decreased latency to immobility in the forced swim stress behavioral test. In addition, pre-exposure to a 1 mg/kg dose of MPH appears to have sensitized the BDNF response to nicotine in females as compared to all other groups. 2 DEDICATION This dissertation is dedicated to my mentor Dr. Russ Brown. I would like to thank him for his advice and support throughout my graduate studies. Dr. Brown introduced me to seven attributes when I joined his lab; critical thinking, problem solving, time management, commitment, desire, precision and the same ―uni‖ policy. Thankfully, he not only taught me the value of these attributes but had the patience for me to learn them. In addition, he has been an extraordinary role model in both my scientific and personal life. Dr. Brown has inspired me to not only formulate good scientific questions but to approach them in the most thoughtful manner. I am forever grateful for his devotion to mentoring, his energy for science, and his passion to keep discovering. This work has been a joint endeavor and a true honor. ―Working hard for something we don’t care about is called stress; working hard for something we love is called passion.‖ -Simon Sinek 3 ACKNOWLEDGEMENTS Firstly, I would like to specifically thank and acknowledge Dr. Matt Palmatier who has been like a second mentor to me. Dr. Palmatier always kept his door open for me to ask scientific and non-scientific questions. I will always value your guidance and role in guiding my scientific path. I would also like to specially thank Dr. Sellers for his willingness to help guide me in my quest for better ―wordsmithing‖ techniques. I would also like to acknowledge and thank Drs. Webb and Kostrzewa for their scientific input and valuable guidance. All members of my committee have inspired unique aspects of my scientific development. I would like to convey my appreciation to all members of Dr. Brown’s lab, both present and past; Blake Griffin, Rob Becker, Ross Roeding, Kate Burgess, Kristen Leedy, Liza Hernandez, Caitlyn De Pre, Leigh Kassem, Daniel Peterson and Seth Kirby. Kristen, I was honored to have you by my side during part of this journey. When you meet someone who shows you a part of yourself you did not know existed, you are forever changed. For that, I will forever be thankful. Liza, thank you for the many long days of behavioral testing and the support you have given me. Leigh, you will always be the water maze diva. Go, Lt. Dan! Seth, thank you for all your support and friendship, I am forever grateful. Lastly, but certainly not least, Daniel, it has been a journey I won’t soon forget. No matter our different approaches to science, at the end of the day, you always held my hand through those life moments. You will always be a memorable part of my graduate school career. I would also like to acknowledge and thank Curtis Bradley; you have been an amazing friend and support system for me. I cannot express what that has meant to me and am honored to call you my friend. None of this would have been possible without the support of my mentor Dr. Brown or my family. Words are not enough to express my gratitude. 4 TABLE OF CONTENTS Page ABSTRACT ….…………………………………………………………………………………...2 DEDICATION .................................................................................................................................3 ACKNOWLEDGEMENTS .............................................................................................................4 Chapter 1. INTRODUCTION ............................................................................................................10 Mechanisms of MPH ..................................................................................................11 Mechanisms of Nicotine .............................................................................................11 ADHD & Smoking .....................................................................................................12 MPH & Nicotine .........................................................................................................13 The Adolescent Brain .................................................................................................17 The Dopamine System ................................................................................................20 Sex Differences in the Dopaminergic System ............................................................22 Sex Differences and Response to Psychostimulants ...................................................23 Neurotrophic Factors and Drug Use ...........................................................................24 The Adolescent Rat .....................................................................................................25 Behavioral Sensitization .............................................................................................27 Forced Swim Test .......................................................................................................29 Conditioned Place Preference .....................................................................................30 Research Questions Addressed in this Dissertation ....................................................32 2. METHODS .......................................................................................................................35 5 Subjects ......................................................................................................................35 Drug Dosage .......................................................................................................35 Drug Treatment ...................................................................................................35 Pre-exposure ...................................................................................................35 Adolescent .......................................................................................................36 Apparatus ...................................................................................................................36 Behavioral Sensitization Apparatus ................................................................36 Conditioned Place Preference (CPP) Apparatus .............................................36 Procedure ...................................................................................................................38