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Dopamine and Norepinephrine Transporter Inhibition in Cocaine Addiction: Using Mice

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Dopamine and Norepinephrine Transporter Inhibition in Cocaine Addiction: Using Mice Expressing Cocaine-Insensitive Transporters DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Bradley Joseph Martin, B.S. Neuroscience Graduate Studies Program The Ohio State University 2011 Dissertation Committee: Howard Haogang Gu, PhD., Advisor Gary L. Wenk, PhD Lane J. Wallace, PhD Robert L. Stephens, Jr., PhD Copyright by Bradley Joseph Martin 2011 Abstract Cocaine’s effects are predominately mediated by inhibiting the reuptake transporters for dopamine, serotonin, and norepinephrine. How each of these transporters contributes to cocaine’s effects is unclear, but such knowledge would aid in efforts to design rational treatments for cocaine addiction. To directly test the contribution of each of these transporters in cocaine’s effects, three transgenic knockout mouse lines were previously created wherein each transporter gene was individually deleted. These knockout mice studies suggest that no single transporter is critical for mediating cocaine’s rewarding effects. However, this hypothesis contradicts pharmacological studies which indicate that the dopamine transporter (DAT) is critical for cocaine’s rewarding effects. Our lab hypothesized that the compensatory adaptations of knockout mice were responsible for this discrepancy. To avoid compensatory adaptations, our lab developed transporter knockin mice expressing a mutated, yet functional, transporter that is insensitive to cocaine inhibition. Unlike transporter knockout mice, these cocaine-insensitive transporter mice retain functioning neurotransmitter systems. We have previously used cocaine-insensitive dopamine transporter mice to reestablish the hypothesis that inhibiting the dopamine transporter is critical for cocaine’s rewarding effects. ii In this dissertation, I will utilize two knockin mouse lines to further elucidate how inhibiting DAT and norepinephrine transporter (NET) contribute to cocaine’s effects. First, I used Golgi-Cox techniques to demonstrate that dopamine transporter cocaine insensitive (DAT-CI) mice do not show chronic cocaine-induced increases in spine density on the dendrites of neurons in the nucleus accumbens relative to wild-type mice. These data suggest that DAT inhibition is critical for cocaine’s ability to produce long- lasting neural adaptations that have been associated with addiction. Second, I performed various molecular, biochemical, and neurochemical techniques to show NET-CI mice are valid tools for studying cocaine addiction. Third, by characterizing the behaviors of NET- CI mice, I found that NET-CI mice have lower levels of basal locomotion, higher levels of locomotor activity in response to cocaine, and similar reward-related behaviors. These data suggest that NET inhibition influences cocaine’s stimulating but not its rewarding effects. Collectively, these studies further our understanding of how the inhibition of DAT and NET contributes to cocaine’s many effects. In addition, our data clarify the literature by demonstrating that NET does not play a major role in cocaine reward. iii Dedication To my wife, Amanda, and my mother, Jeannie. iv Acknowledgments I would like to thank my advisor, Dr. Howard Gu, for adopting me into his lab, for being patient and supportive, and for taking on the Sisyphean task of trying to teach molecular biology to a psychology student. I would also like to thank the professors who served on my committees, Drs. Gary Wenk, Lane Wallace, Robert Stephens, Georgia Bishop, and David Saffeen, for their encouragement and feedback - a special thanks to Dr. Wallace for giving me plenty of guidance and opportunities to teach. I would also like to thank my labmates: Drs. Erik Hill, Hua Wei and Michael Tilley; Keerthi Thirtamara, Bartholomew Naughton, Pauline Chen, Dawn Han, Aravand Menon, Daniel Yoon, and Brian O’Neill. A special thanks to Brian for always challenging me and to Hua for creating the cocaine-insensitive norepinephrine transporter mice. I would also like to thank my collaborators Drs. A. Courtney Devries, and Dr. Maria Hadjiconstantinou Neff. I would like to thank my family and friends; my mother for managing to provide for my brother and I as a single mother; my brother, Alex; my grandparents, Frank and Bryan Wool, for showing me the value of an education; my dad, Jon Hackett, and my step father, Rusty Van Leuven, for always being proud of me; my wife’s grandparents, Dr. Bill and Helen Swank and Frank and Marcy Webster, and parents, Dr. Douglas and Theresa Webster for making Columbus a wonderful place to live and for doting on our v children; my friends Daniel Hendrix, Leonard Greco, Joe Piasick, Dr. Ryan Smith, and Dr. Michael Stone. I would like to thank my wife, Amanda Martin, for being so supportive and not judging me too much during the ups and downs of this endeavor. vi Vita January 22nd, 1982 .........................................Born, Jacksonville, Florida 2000................................................................Cornwall Central High School 2004................................................................Colorado State University 2005 ...............................................................Postbac Intramural Research Training Award (IRTA) recipients 2006 to Present ..............................................Graduate Research Associate, Department of Psychiatry and Pharmacology, The Ohio State University Publications Martin BJ, Wei H., Gu HH. Characterizing cocaine reward and stimulation in mice expressing cocaine-insensitive norepinephrine transporter. (in prep) Martin BJ, Naughton BJ., Thirthamar, KK. Devries AC., Gu. HH. Dopamine transporter inhibition is necessary for cocaine’s ability to increase dendritic spine density in the nucleus accumbens. Synapse. 2011 Jun; 65(6):490-6. vii Bruno JP, Gash C, Martin B, Zmarowski A, Pomerleau F, Burmeister J, Huettl P, Gerhardt GA. Second-by-second measurement of acetylcholine release in prefrontal cortex. European Journal of Neuroscience. 24(10), 2749-57, 2006 Wendland JR, Martin BJ, Kruse MR, Lesch KP, Murphy DL. Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531. Mol Psychiatry 11(3), 2006. Kim DK, Tolliver TJ, Huang SJ, Martin BJ, Andrews AM, Wichems C, Holmes A, Lesch KP, Murphy, DL. Altered serotonin synthesis, turnover and dynamic regulation in multiple brain regions of mice lacking the serotonin transporter. Neuropharmacology. 2005 Nov; 49(6):798-810. Fields of Study Major Field: Neuroscience Graduate Studies Program viii Table of Contents Abstract ............................................................................................................................... ii Dedication .......................................................................................................................... iv Acknowledgments .............................................................................................................. v Vita .................................................................................................................................... vii Publications ....................................................................................................................... vii Table of Contents ............................................................................................................... ix List of Figures .................................................................................................................... xi Chapter 1: Introduction to animal models of cocaine addiction ......................................... 1 Chapter 2: Dopamine Transporter Inhibition is Necessary for Cocaine-Induced Increases in Dendritic Spine Density in the Nucleus Accumbens .................................................... 22 2.1 Background and Introduction .................................................................................. 22 2.2 Materials and Methods ............................................................................................ 25 2.3 Results ..................................................................................................................... 28 2.4 Discussion ............................................................................................................... 30 Chapter 3: Characterizing cocaine reward and stimulation in mice expressing cocaine- insensitive norepinephrine transporter. ............................................................................. 40 3.1 Background and Introduction .................................................................................. 40 ix 3.2 Materials and Methods ............................................................................................ 42 3.3 Results ..................................................................................................................... 47 3.4 Discussion ............................................................................................................... 49 Chapter 4: General discussion and future direction .......................................................... 63 References ......................................................................................................................... 71 Abbreviations .................................................................................................................... 91 x List of Figures Figure
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