Dopamine D1 and D3 Receptor Polypharmacology in Cocaine Reward and Cocaine Seeking
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City University of New York (CUNY) CUNY Academic Works All Dissertations, Theses, and Capstone Projects Dissertations, Theses, and Capstone Projects 2-2017 Dopamine D1 and D3 Receptor Polypharmacology in Cocaine Reward and Cocaine Seeking Ewa J. Galaj The Graduate Center, City University of New York How does access to this work benefit ou?y Let us know! More information about this work at: https://academicworks.cuny.edu/gc_etds/1844 Discover additional works at: https://academicworks.cuny.edu This work is made publicly available by the City University of New York (CUNY). Contact: [email protected] DOPAMINE D1 AND D3 RECEPTOR POLYPHARMACOLOGY IN COCAINE REWARD AND COCAINE SEEKING by EWA GALAJ A dissertation submitted to the Graduate Faculty in Psychology in partial fulfillment of the requirements for the degree of Doctor of Philosophy, The City University of New York, 2017 ii © 2017 Ewa Galaj All Rights Reserved iii D1 AND D3 RECEPTOR POLYPHARMACOLOGY IN COCAINE REWARD AND COCAINE SEEKING by EWA GALAJ This manuscript has been read and accepted for the Graduate Faculty in Psychology in satisfaction of the dissertation requirements for the degree of Doctor of Philosophy. _____________Date Dr. Robert Ranaldi________________________ Chair of Examining Committee _____________Date Dr. Richard Bodnar_________________________ Executive Officer Supervisory Committee Dr. Richard Bodnar_________________________________ Dr. Carolyn Pytte___________________________________ Dr. Kenneth Carr___________________________________ Dr. Grace Rossi____________________________________ THE CITY UNIVERSITY OF NEW YORK iv ACKNOWLEDGEMENTS I would like to express my deep appreciation and gratitude to my advisor, Dr. Robert Ranaldi, for his patience and mentorship. I am truly fortunate to have had the opportunity to work with him and to learn what good science is. I would like to thank him for his patient teaching on how to think critically and to write in clear, focused manner. I am very grateful for his confidence and continuous support, especially in times of discouragement and doubt. Without his guidance and help this dissertation would not have been possible. I also want to thank the members of my dissertation committee: Drs. Carolyn Pytte, Richard Bodnar, Kenneth Carr and Grace Rossi for their guidance on this project. I am very thankful to Dr. Rossi for the support and encouragement that she gave me on pursuing a doctoral degree. Very special thanks go to Monica Manuszak who provided exceptional dedication and assistance on many projects that we worked on together. I also would like to acknowledge other students in Dr. Ranaldi’s laboratory who provided technical support in various ways: Sandra Babic, Neal Suppersaad, Ali Shukur, Jordan Schachar, David Arastehmanesh, Joseph Haynes and Ivonne Cruz. Lastly, I want to thank my siblings, Beata Arnold and Marek Galaj, for their endless support in this challenging process. This dissertation is dedicated to my mother, Rozalia Galaj. v PREFACE Portions of this dissertation have been accepted for publication. Chapters 2 and 3 consist of text and data that have been accepted for publication by the peer-review journal Psychopharmacology in August of 2016. The manuscript titled “Dopamine D1 and D3 receptor interaction in cocaine reward and seeking in rats” was co-authored with Drs. Wayne Harding and Robert Ranaldi. vi Dopamine D1 and D3 receptor polypharmacology in cocaine reward and cocaine seeking ABSTRACT Advisor: Professor Robert Ranaldi Background: In the search for efficacious pharmacotherapies to treat cocaine addiction much attention has been given to agents targeting D1 or D3 receptors because of the involvement of these receptors in cocaine-related behaviors. D1 and D3 receptor partial agonists and antagonists have been shown to reduce cocaine reward, reinstatement of cocaine seeking and conditioned place preference (CPP) in rodents and non-human primates. However, translation of these encouraging results with selective D1 or D3 receptor agents has been limited due to a number of factors including toxicity, poor pharmacokinetic properties and extrapyramidal and sedative side effects. Purpose: Given the role of D1 and D3 receptors in cocaine-related behaviors and the urgent need for effective anti-cocaine treatments, it is important that we continue to pursue new pharmacological approaches such as the combinations of compounds that have differential functions at multiple dopamine receptors. The aims of this dissertation were to evaluate the effects of the novel strategy of simultaneous treatments with a D3 receptor antagonist (NGB 2904) and D1 receptor partial agonist (SKF 77434) in animal models of drug addiction, including cue-induced reinstatement of cocaine seeking, cocaine conditioned place preference (CPP) and cocaine self-administration in rats. vii Methods: In the reinstatement experiment, rats underwent cocaine self-administration training followed by extinction and a cue-induced reinstatement test. Prior to the reinstatement test rats were treated with one of several doses of NGB 2904, SKF 77434 or the combination of the two and their lever presses were measured. In the CPP experiment rats were conditioned to experience cocaine in one compartment of a CPP apparatus and saline in the other. After conditioning rats were treated with the same compounds alone or combined prior to the CPP test. The time spent in the cocaine-paired compartment prior to and after conditioning was measured as an indication of cocaine CPP. In the self-administration experiment, rats were trained to self-administer cocaine under a progressive ratio (PR) schedule of reinforcement. After demonstrating stable baseline break points (BPs) rats were treated repeatedly with NGB 2904 or SKF 77434 alone or the combination of the two. Results: The co-administration of NGB 2904 and SKF 77434, at doses which when administered individually produced no significant effects, prior to reinstatement or CPP tests significantly reduced lever pressing and time spent in the cocaine-paired environment, suggesting synergistic effects of the combined compounds on their abilities to reduce cocaine seeking. When administered to rats self-administering cocaine under a PR schedule of reinforcement doses of NGB 2904 which were ineffective alone significantly potentiated the break point-reducing effects of SKF 77434. Conclusions: The results of this study indicate that the combined treatment with a D1 receptor partial agonist and D3 receptor antagonist produces robust decreases in cocaine seeking and reward. These effects provide insight into a novel therapeutic approach to treat cocaine addiction. viii TABLE OF CONTENTS List of Figures.………………………………………………………..……….……..xi 1. Chapter 1- General Introduction …………………………………………………......1 1.1. Understanding drug abuse and addiction…………………………………………......1 1.2. Dopamine and drug reward…………………………………………………………...3 1.3. Dopamine receptors: subtypes, signaling and location…………………………..…...9 1.4. D1 receptors in reward ……………………………………………………………...13 1.5. The role of D1 receptors in conditioned place preference…………………………..18 1.6. D1 receptors and reinstatement of drug seeking…………………………………….21 1.7. D3 receptors in drug reward………………………………………….…...………...24 1.8. D3 receptors and CPP……………………………………………………………….30 1.9. D3 receptors and drug seeking………………………………………………………32 1.10. D1-D3 receptor interactions at the physical, biochemical and functional levels…..35 1.11. D1-D2 receptor heteromers……………………………………………………...…39 1.12. Current pharmacological strategies and possible directions in drug addiction treatment………………………………………………………………………...…..43 1.13. Specific Aims………………...…………………………………………………….45 2. Chapter 2. Simultaneous D1 receptor partial agonism and D3 receptor antagonism reduce cue-induced reinstatement of cocaine seeking and conditioned place preference……………………………………………………………………………46 2.1. Introduction………………………………………………………………………….46 2.2. Methods………...……………………………………………………………………48 2.2.1. Subjects……………………………………………………………………………48 ix 2.2.2. Surgery…………………………………………………………………………….49 2.2.3. Apparatus………………………………………………………………………….50 2.2.4. Drugs………………………………………………………………………………51 2.2.5. Procedure………………………………………………………………………….51 Experiment 1: Cue-induced reinstatement of cocaine seeking……………………51 Experiment 2: Cocaine conditioned place preference…………………………….52 2.2.6. Data analysis………………………………………………………………………53 2.3. Results...………………………………………………………………...…………..54 Experiment 1: Cue-induced reinstatement of cocaine seeking……………….……54 Experiment 2: Cocaine conditioned place preference…………………………......56 2.4. Discussion…………………………...……………………………………………...61 3. Chapter 3. Interaction of D1 and D3 receptors in cocaine reward ……….....……...63 3.1. Introduction………………………………………...……………………………….63 3.2. Methods……………………………………………………...……………………..65 3.2.1. Subjects……………………………………………………………………………65 3.2.2. Surgery…………………………………………………………………………….65 3.2.3. Apparatus………………………………………………………………………….66 3.2.4. Drugs………………………………………………………………………………66 3.2.5. Procedure……………………………………………………………………….....67 Experiment 3: Cocaine self-administration under the PR schedule (cocaine reward)………………………………………………………………………….…67 3.2.6. Data analysis………………………………………………………………………68 x 3.3. Results of Experiment 3: Cocaine self-administration under a PR schedule of reinforcement (cocaine reward)……………………………………………….…..68 3.4. Discussion…………………………………………………………………...……....71 4. Chapter 4. General Discussion…………………………………………...……….…72 4.1. Conclusions……………………………………………………………………….…81 4.2. Implications and