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Discriminative and Reinforcing Effects of Cocaine-Levamisole Combinations

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Discriminative and Reinforcing Effects of Cocaine-Levamisole Combinations Western Michigan University ScholarWorks at WMU Dissertations Graduate College 6-2017 Discriminative and Reinforcing Effects of Cocaine-Levamisole Combinations Zachary J. Zimmermann Western Michigan University, [email protected] Follow this and additional works at: https://scholarworks.wmich.edu/dissertations Part of the Substance Abuse and Addiction Commons Recommended Citation Zimmermann, Zachary J., "Discriminative and Reinforcing Effects of Cocaine-Levamisole Combinations" (2017). Dissertations. 3120. https://scholarworks.wmich.edu/dissertations/3120 This Dissertation-Open Access is brought to you for free and open access by the Graduate College at ScholarWorks at WMU. It has been accepted for inclusion in Dissertations by an authorized administrator of ScholarWorks at WMU. For more information, please contact [email protected]. DISCRIMINATIVE AND REINFORCING EFFECTS OF COCAINE-LEVAMISOLE COMBINATIONS by Zachary J. Zimmermann A dissertation submitted to the Graduate College in partial fulfillment of the requirements for the degree of Doctor of Philosophy Psychology Western Michigan University June 2017 Dissertation Committee: Alan Poling, Ph.D., Chair Lisa Baker, Ph.D. David V. Gauvin, Ph.D. Cynthia Pietras, Ph.D. DISCRIMINATIVE AND REINFORCING EFFECTS OF COCAINE-LEVAMISOLE COMBINATIONS Zachary J. Zimmermann, Ph.D. Western Michigan University, 2017 The behavioral and neurochemical effects of cocaine are well established, and it is one of the most widely abused illicit drugs. Illicit cocaine is often adulterated with levamisole, which is an anthelmintic that was withdrawn from the U. S. market in 2000. It has been hypothesized that levamisole, unlike other common adulterants which are added as simple bulking agents, has effects of its own which may be responsible for its use as an adulterant. Although these effects are speculative, the addition of levamisole to cocaine has become an increasing public health concern, as serious adverse effects (e.g., vasculitis, neutropenia) of levamisole-adulterated cocaine have been observed in drug users. The present experiments were intended to provide further information about effects of levamisole that may help to explain its use as an adulterant. The aim of the first experiment was to determine if adding levamisole alters cocaine self-administration in rats. To this end, the response patterns of rats trained to self-administer cocaine were examined to determine whether they were altered by pretreatment with two doses of levamisole (1 and 10 mg/kg). Although response patterns were generally unaffected, animals consistently consumed less cocaine at all doses tested under both pretreatment conditions. This decrease in responding suggests that levamisole is not added to directly increase cocaine intake. The aim of the second experiment was to examine how adding levamisole affected the discriminative stimulus properties of cocaine. Rats were trained to discriminate between cocaine and saline injections to earn food in a classic drug discrimination procedure. Various doses of cocaine, levamisole, and cocaine-levamisole combinations were then tested to yield cross- generalization profiles. Levamisole alone failed to produce cocaine-appropriate responding in the majority of animals, but did so in a dose-dependent manner for a small minority. Cocaine- levamisole combinations consistently produced dose-dependent cocaine-appropriate responding, and did so to a greater extent than did the constituent cocaine or levamisole dose alone (i.e., supra-additivity). The results of these studies are consistent with the popular notion that levamisole is added to cocaine to alter its effects, rather than simply as a bulking agent. Furthermore, these results indicate that a supra-additive interaction between cocaine and levamisole exists with regard to their discriminative stimulus effects. Further research into the behavioral and neurochemical mechanisms of action of cocaine-levamisole combinations is warranted. ©2017 Zachary J. Zimmermann ACKNOWLEDGMENTS I am forever indebted to my wife, Abby, and my parents, Ken and Sherry, for their support throughout all of this. I would not have been able to embark upon this journey without their complete trust, guidance, and unbelievable patience. I want to thank Dr. Al Poling for helping me to develop into the skeptical thinker and behavioral scientist I am today. The freedom and opportunities afforded to me as your student have honestly been life changing, and for that I cannot be more appreciative. I also need to thank Dr. Lisa Baker for cultivating my interest in behavioral pharmacology years ago, and Dr. Cindy Pietras for exposing me to behavior analysis and presenting me with some of the most important opportunities in the beginning of my graduate career. Finally, I must thank Dr. David Gauvin, for taking me under his wing and providing me with invaluable teaching experiences. Without all of your unwavering support and willingness to challenge me, I could not have successfully completed this project. Lastly, I must acknowledge all of the previous and current lab members of both Poling and Baker labs with whom I have grown close. You all have provided me with valuable feedback, frequent learning opportunities, and a collaborative research environment for which I am grateful to have been a part of. Zachary J. Zimmermann ii TABLE OF CONTENTS ACKNOWLEDGMENTS .............................................................................................................. ii LIST OF TABLES ......................................................................................................................... vi LIST OF FIGURES .......................................................................................................................vii CHAPTER I. INTRODUCTION ..................................................................................................................1 General Background ............................................................................................................1 Cocaine ................................................................................................................................1 Production and distribution ......................................................................................1 Adulteration and drug manufacturing ......................................................................3 Pharmacology ..........................................................................................................4 Levamisole ...........................................................................................................................4 Pharmacology ..........................................................................................................6 Complications related to levamisole-adulterated cocaine use ................................9 Potentiation of drug effects ...................................................................................10 Analysis of drug interactions ................................................................................11 Behavioral Models .............................................................................................................14 Self-administration ................................................................................................14 Interaction effects ......................................................................................16 Drug discrimination ..............................................................................................18 Interaction effects ......................................................................................20 Behavioral Literature ........................................................................................................22 iii Table of Contents — Continued CHAPTER II. EXPERIMENT 1: EFFECTS OF LEVAMISOLE ON COCAINE SELF- ADMINISTRATION IN SPRAGUE-DAWLEY RATS.........................................................25 Overview ............................................................................................................................25 Methods..............................................................................................................................25 Subjects ..................................................................................................................25 Apparatus ...............................................................................................................27 Procedure ...........................................................................................................................28 Catheter maintenance .............................................................................................28 Response acquisition ..............................................................................................29 Cocaine training .....................................................................................................29 Cocaine testing .......................................................................................................30 Levamisole testing .................................................................................................31 Drugs ......................................................................................................................31 Data analysis ..........................................................................................................31 Results ................................................................................................................................32
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