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Opiate-Induced Neuroplastic Alterations to Dopamine Signaling in the Basolateral Amygdala-Prefrontal Cortical Pathway

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Opiate-Induced Neuroplastic Alterations to Dopamine Signaling in the Basolateral Amygdala-Prefrontal Cortical Pathway Western University Scholarship@Western Electronic Thesis and Dissertation Repository 10-19-2017 11:00 AM Opiate-Induced Neuroplastic Alterations to Dopamine Signaling in the Basolateral Amygdala-Prefrontal Cortical Pathway Laura G. Rosen The University of Western Ontario Supervisor Steven Laviolette The University of Western Ontario Co-Supervisor Walter Rushlow The University of Western Ontario Graduate Program in Neuroscience A thesis submitted in partial fulfillment of the equirr ements for the degree in Doctor of Philosophy © Laura G. Rosen 2017 Follow this and additional works at: https://ir.lib.uwo.ca/etd Recommended Citation Rosen, Laura G., "Opiate-Induced Neuroplastic Alterations to Dopamine Signaling in the Basolateral Amygdala-Prefrontal Cortical Pathway" (2017). Electronic Thesis and Dissertation Repository. 4984. https://ir.lib.uwo.ca/etd/4984 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. Abstract Opiate addiction is a chronic disorder with high rates of relapse. The failure to maintain sobriety after prolonged abstinence is believed to be due in part to the persistence of potent memories associated with the drug-taking experience. Activation of these memories by re- exposure to drug-related cues can trigger craving in many individuals. Thus, understanding the neurobiological processes underlying the formation of these memories may provide insight into the persistence of addiction. The mammalian basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) comprise a functionally interconnected circuit that is critical for processing opiate-related associative memories. There is some evidence that chronic opiate exposure results in alterations to the function of dopamine (DA) D1 and D2 receptors and their intracellular targets within the BLA, but critical questions remain in regards to these effects within the BLA-mPFC circuit. For instance, opiate-induced alterations to intra-mPFC DA signaling in the context of associative opiate memories has not yet been explored. Furthermore, the role of the DA D3 receptor has not yet been investigated. Finally, there is little understanding of the temporal dynamics underlying these changes in DAergic signaling. Using behavioural models of associative memory formation (conditioned place preference and conditioned place aversion) paired with analyses of protein expression, we further characterized how chronic opiate exposure results in neuroplastic changes to DA receptor expression and signaling in the BLA-mPFC pathway. Here, we report that chronic opiate exposure results in a series of alterations to D1, D2 and D3 signaling within the BLA-mPFC circuit in the context of both opiate reward and withdrawal aversion memories. Specifically, we highlighted the importance of D2 and CaMKIIα signaling within the mPFC, identified the role of intra-BLA D3-Cdk5-calcineurin signaling in reward and aversion memory formation, and temporally mapped opiate-induced alterations to intra-BLA memory molecules. Together, these results provide a more complete understanding of how opiate exposure profoundly alters DA signaling between the dependent and non-dependent states. Interestingly, we found that many of the changes induced by chronic opiate exposure are not only transient, but may be functionally reversible, thus providing an avenue for future development of pharmacological interventions for opiate addiction. Keywords addiction, associative memory, aversion learning, basolateral amygdala, conditioned place aversion, conditioned place preference, D1 receptor, D2 receptor, D3 receptor, dopamine, medial prefrontal cortex, opiate addiction, opiates, reward learning, western blotting ii Co-Authorship Statement Chapter 2: Entitled “Opiate Exposure State Controls a D2-CaMKIIα-Dependent Memory Switch in the Amygdala-Prefrontal Cortical Circuit” was written by Laura G. Rosen with inputs from Steven R. Laviolette and Walter J. Rushlow. Experimental procedures and data analysis were performed by Laura G. Rosen with assistance from Jordan Zunder, Justine Renard, Jennifer Fu and Walter Rushlow. Steven R. Laviolette and Walter J. Rushlow provided intellectual input. Chapter 3: Entitled “Opiate exposure state controls dopamine D3 receptor and cdk5/calcineurin signaling in the basolateral amygdala during reward and withdrawal aversion memory formation” was written by Laura G. Rosen with inputs from Steven R. Laviolette and Walter J. Rushlow. Experimental procedures and data analysis were performed by Laura G. Rosen and Walter J. Rushlow. Steven R. Laviolette and Walter J. Rushlow provided intellectual input. Chapter 4: Entitled “A temporal analysis of opiate-induced alterations to intra-BLA signaling molecules implicated in the formation of associative drug memories” was written by Laura G. Rosen with inputs from Steven R. Laviolette and Walter J. Rushlow. Experimental procedures and data analysis were performed by Laura G. Rosen and Walter J. Rushlow. Steven R. Laviolette and Walter J. Rushlow provided intellectual input. iii Acknowledgments Firstly, I would like to thank my supervisors, Dr. Steven Laviolette and Dr. Walter Rushlow, for their generosity, guidance and mentorship over the course of my PhD studies. I have grown and developed as both a scientist and a person during my time at Western, and I owe much of this growth to them. Next, I would like to thank the members of my advisory committee: Dr. Derek Mitchell, Dr. Martin Kavaliers, and Dr. Arthur Brown. Their insight and advice was integral to the completion of this work. I have had the pleasure of working with a number of very fine labmates and collaborators, and wish them all the greatest success. A special thank you to those who also became close friends: Jordan Zunder, Dr. Tasha Ahmad, Dr. Michael Loureiro, Dr. Cecilia Kramar, and Dr. Justine Renard. My life has been forever enriched by having you in it. To my friends near and far, your care and encouragement helped to push me forward when I doubted myself the most. “Thank you” is not nearly enough for all that you have helped me accomplish. Joel, you are the primary source of both my laughter and my strength. Your support makes my world a brighter place. Thank you for helping me to see the finish line and to finally cross it. None of this work would be possible without the unconditional love and support of my family. To my parents, Michael and Viv: you have helped me grow and achieve goals that would be impossible without you. To show my gratitude, I can finally tell you that I think I’m done school for a while. This work is dedicated to my grandma Thelma. I have your genes to thank for my insatiable curiosity. iv Table of Contents Abstract ................................................................................................................................ i Co-Authorship Statement................................................................................................... iii Acknowledgments.............................................................................................................. iv Table of Contents ................................................................................................................ v List of Tables ...................................................................................................................... x List of Figures .................................................................................................................... xi List of Abbreviations ....................................................................................................... xiii List of Appendices ........................................................................................................... xiv Chapter 1 ............................................................................................................................. 1 1 General Introduction ...................................................................................................... 1 1.1 INTRODUCTION TO OPIATE ADDICTION...................................................... 2 1.1.1 Epidemiology .............................................................................................. 2 1.1.2 Opiate Addiction ......................................................................................... 2 1.1.3 Treatment .................................................................................................... 3 1.1.4 Relapse: A Moral Weakness? ..................................................................... 3 1.2 CONCEPTUALIZING ADDICTION: CLINICAL AND NEUROBIOLOGICAL MODELS ................................................................................................................ 4 1.2.1 Disease Model of Addiction ....................................................................... 4 1.2.2 The Dopamine Reward Hypothesis of Addiction ....................................... 5 1.2.3 The Opponent-Process Model of Addiction: Addiction as Hedonic Allostasis ..................................................................................................... 5 1.2.4 The Incentive Salience Model of Addiction ............................................... 6 1.2.5 Addiction as a Disorder of Learning and Memory ..................................... 7 1.2.6 Testing Reward Learning in Animal
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