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Cannabinoid Modulation of Reinforcement Maintained by Stimulation of the Medial Forebrain Bundle in C57bl/6J Mice

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Cannabinoid Modulation of Reinforcement Maintained by Stimulation of the Medial Forebrain Bundle in C57bl/6J Mice Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2013 Cannabinoid Modulation of Reinforcement Maintained by Stimulation of the Medial Forebrain Bundle in C57Bl/6J Mice Jason Wiebelhaus Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Psychology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/555 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. © Jason Michael Wiebelhaus, 2013 All Rights Reserved Cannabinoid Modulation of Reinforcement Maintained by Stimulation of the Medial Forebrain Bundle in C57Bl/6J Mice Dissertation to be submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University By: Jason M. Wiebelhaus Master of Science, Virginia Commonwealth University, 2009 Bachelor of Science, University of WI-Eau Claire, 2006 Co-Directors: Aron H. Lichtman1, Ph.D. and Joseph H. Porter2, Ph.D. 1, 2Professors 1Department of Pharmacology and Toxicology, 2Department of Psychology Virginia Commonwealth University Richmond, VA September, 2013 ii Acknowledgement I owe my thanks to many people who helped me throughout the process of conducting these experiments and writing my dissertation. First and foremost I would like to thank my mentor and dissertation co-director director Aron H. Lichtman for his guidance and patience throughout my years of graduate school at Virginia Commonwealth University. I would also like to thank my committee members Joseph H. Porter, Robert J. Hamm, Laura J. Sim-Selley, S. Stevens Negus, Scott R. Vrana and Laura E. Wise for their teachings, suggestions and support that led to vast improvements with these studies. I must also extend my gratitude to fellow graduate students and colleagues including, Matt Walentiny, Tom Gamage, Sudeshna Ghosh, Travis Grim, Allen Owens, Matt Lazenka, Andrew Kwilasz, and Jon Warner for their stimulating ideas and contributions to this work. They have provided me with many insights and words of advice that contributed to the success of these studies. I would also like to acknowledge my undergraduate research advisor Dr. David C. Jewett for teaching me the foundations behavioral pharmacology, and spurring my interest in becoming a scientist. Last, but not least, I would like to thank my parents, Ron and Eileen Wiebelhaus, my brother, David and my sister Noelle for their endless support, and especially their willingness to listen. This work would not have been possible without all of their contributions. iii Table of Contents Page Acknowledgement .............................................................................................................. ii List of Tables ......................................................................................................................v List of Figures .................................................................................................................... vi Abstract………. .............................................................................................................. .viii I. Introduction ......................................................................................................................1 Endogenous Cannabinoid System...........................................................................1 Endocannabinoids ...................................................................................................2 AEA and 2-AG: Distinct Endocannabinoids ..........................................................6 Behavioral Effects of MAGL Inhibition…. ............................................................8 Behavioral Effects of FAAH inhibition ................................................................10 Behavioral Effects of Combined FAAH and MAGL inhibition ...........................11 Cannabinoids and Reward ....................................................................................12 Preclinical Models of Reinforcement and Reward-Associated Behavior .............13 Self-administration ................................................................................................13 Conditioned Place Preference ...............................................................................14 Intracranial Self-Stimulation .................................................................................15 Cannabinoid Activity in the Mesolimbic System .................................................24 II. Rationale…....................................................................................................................28 III. Methods........................................................................................................................31 Subjects..... ............................................................................................................31 Drugs........... ..........................................................................................................32 Apparatus… ..........................................................................................................32 Stereotaxic Surgery... ............................................................................................33 Behavioral Procedures ..........................................................................................34 Spontaneous Locomotor Activity .........................................................................34 Operant Responding for Food ...............................................................................34 ICSS ......................................................................................................................35 Analytical Procedures ...........................................................................................37 Tissue Extraction and Quantification of AEA, 2-AG and AA .............................37 Data Analysis ........................................................................................................39 IV. Results..........................................................................................................................40 Cocaine ICSS Dose-Response Assessment.. ........................................................40 THC ICSS Experiments ........................................................................................43 THC Dose-Response Assessment…. ....................................................................43 THC Time-Course Assessment.............................................................................49 THC: Evaluation of CB1 Receptors ......................................................................54 THC: Evaluation of CB2 Receptors ......................................................................58 iv THC: Operant Responding for Food Assessment .................................................61 JZL184 ICSS Experiments ...................................................................................63 JZL184 Dose-Response Assessment ....................................................................63 JZL184 Time-Course Assessment ........................................................................68 JZL184: Evaluation of CB1 receptors ...................................................................71 JZL184: Evaluation of CB2 receptors ...................................................................75 JZL184 Operant Responding for Food Assessment .............................................78 JZL184 Spontaneous Locomotor Activity Assessment ........................................79 JZL184 Endocannabinoid Quantification .............................................................82 PF-3845 ICSS Experiments ..................................................................................85 PF-3845 Dose-Response Assessment ...................................................................85 PF-3845 Time-Course Assessment .......................................................................90 PF-3845: Evaluation of CB1 Receptors ................................................................93 PF-3845: Evaluation of CB2 Receptors ................................................................97 SA-57 ICSS Experiments ...................................................................................101 SA-57 Dose-Response Assessment ....................................................................101 SA-57 Time-Course Assessment ........................................................................105 SA-57: Evaluation of CB1 receptors ...................................................................109 SA-57: Evaluation of CB2 receptors ...................................................................113 SA-57 Spontaneous Locomotor Activity Assessment ........................................116 SA-57 Endocannabinoid Quantification .............................................................118 V. Discussion...... ............................................................................................................122 Cocaine ................................................................................................................123 CB1 and CB2 Antagonists ....................................................................................125
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