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Discriminative Stimulus Effects of 3,4-Methylenedioxypyrovalerone and 4-Methylmethcathinone

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Discriminative Stimulus Effects of 3,4-Methylenedioxypyrovalerone and 4-Methylmethcathinone Western Michigan University ScholarWorks at WMU Dissertations Graduate College 8-2016 Discriminative Stimulus Effects of 3,4-Methylenedioxypyrovalerone and 4-Methylmethcathinone Michael D. Berquist Western Michigan University, [email protected] Follow this and additional works at: https://scholarworks.wmich.edu/dissertations Part of the Experimental Analysis of Behavior Commons Recommended Citation Berquist, Michael D., "Discriminative Stimulus Effects of 3,4-Methylenedioxypyrovalerone and 4-Methylmethcathinone" (2016). Dissertations. 1962. https://scholarworks.wmich.edu/dissertations/1962 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 STIMULUS EFFECTS OF 3,4-METHYLENEDIOXYPYROVALERONE AND 4-METHYLMETHCATHINONE Michael D. Berquist II, Ph.D. Western Michigan University, 2016 Recent escalation in the popularity of recreational synthetic cathinone (“bath salts”) use has prompted numerous scientific investigations of the neurochemical and behavioral effects of 3,4-methylenedioxypyrovalerone (MDPV) and 4-methylmethcathinone (4-MMC), two of the more common chemical constituents of these illicit “bath salts”. Previous neurochemical and electrophysiological studies have revealed that MDPV functions as a blocker, and 4-MMC as a substrate, at monoamine transporters, and both produce transient increases in extracellular monoamines. In addition, previous research has demonstrated that MDPV and 4-MMC support self-administration in nonhuman experimental subjects, and their rewarding effects are observed when paired with contextual cues in nonhuman models of conditioned place preference. Comparatively fewer studies have characterized the discriminative stimulus effects of these drugs using drug discrimination methods. The drug discrimination paradigm is an in vivo drug-detection assay with high predictive validity. To further characterize the discriminative stimulus effects of these synthetic cathinones, the current study trained 16 male Sprague-Dawley rats to discriminate either 0.3 mg/kg MDPV (N = 8) or 1.0 mg/kg 4-MMC (N = 8) from saline. Once the rats met discrimination acquisition criteria, substitution tests were conducted with compounds that function as dopamine releasers (d-amphetamine, (+)-methamphetamine), monoamine transporter inhibitors (MDPV, (-)-cocaine), monoamine transporter releasers (4-MMC, MDMA), a serotonin releaser ((+)-fenfluramine), and an indoleamine hallucinogen (lysergic acid diethylamide, (+)-LSD). Discriminative stimulus control was established in ~35 and ~37 training sessions in the 0.3 mg/kg MDPV group and 1.0 mg/kg 4-MMC group, respectively. In the 0.3 mg/kg MDPV training group, the aforementioned dopamine releasers, monoamine transporter inhibitors, and (+)-fenfluramine produced full substitution, whereas the monoamine transporter releasers and (+)-LSD failed to fully substitute and produced statistical reductions in response rate. In the 1.0 mg/kg 4-MMC training group, all drugs except (+)-LSD and (+)-fenfluramine produced full substitution. Overall, these findings are consistent with human user reports indicating that MDPV and 4-MMC produce interoceptive stimulus effects that are comparable to prototypical drugs of abuse, such as cocaine and MDMA. Future studies with receptor-selective antagonists would be especially valuable to further investigate the neurochemical actions contributing to the discriminative stimulus effects produced by these substances. DISCRIMINATIVE STIMULUS EFFECTS OF 3,4-METHYLENEDIOXYPYROVALERONE AND 4-METHYLMETHCATHINONE by Michael D. Berquist II A dissertation submitted to the Graduate College in partial fulfillment of the requirements for the degree of Doctor of Philosophy Psychology Western Michigan University August 2016 Doctoral Committee: Lisa E. Baker, Ph.D., Chair Alan D. Poling, Ph.D. Bradley E. Huitema, Ph.D. Adam J. Prus, Ph.D. Copyright by Michael D. Berquist II 2016 ACKNOWLEDGEMENTS Many people contributed to the completion of this dissertation. First, I would like to thank my family, especially my mother Belinda Berquist, father Michael Berquist, and sisters Heidi Berquist-Sharp and Brianna Berquist, for their love and support while completing my graduate studies. I also wish to thank my grandparents, Keith and Deanie LeMoine, and Dale and Elaine Berquist, for teaching me important values. And yes, I’ve learned that Grandpa Dale is right: “The hardest thing about anything is thinking about it.” I am a better man because of these people—to everyone, I love you. Second, I am grateful for the guidance throughout graduate school from my dissertation advisor, Dr. Lisa Baker, and my master’s degree advisor, Dr. Adam Prus. I am indebted to my friends Eric Harvey, Zachary Zimmerman, Rachel Burroughs, and Nathyn Thompson for their advice and assistance throughout this study. In addition, I am thankful to the other members of my dissertation committee, Dr. Al Poling and Dr. Brad Huitema, who have helped me become a more skeptical and proficient scientist. Michael D. Berquist II ii TABLE OF CONTENTS ACKNOWLEDGMENTS ..................................................................................................................... ii LIST OF TABLES ............................................................................................................................................ vi LIST OF FIGURES ........................................................................................................................................... vii INTRODUCTION .................................................................................................................................. 1 Drug Use ..................................................................................................................................... 1 Cathinone ..................................................................................................................................... 3 Use, prevalence, and pharmacokinetics ............................................................................ 3 Legal status ....................................................................................................................... 4 Neurochemical profile ....................................................................................................... 4 Psychopharmacology of cathinone .................................................................................... 6 Synthetic Cathinones ................................................................................................................... 10 Description, use, and prevalence ....................................................................................... 10 Previous Research on MDPV and 4-MMC .................................................................................. 12 Electrophysiological and neurochemical effects ............................................................... 12 Polysubstance use in humans ............................................................................................ 13 Locomotor effects and ambulatory sensitization ............................................................... 15 Models of reinforcement and reward ................................................................................ 17 Self-administration ................................................................................................. 20 Intracranial self-stimulation ................................................................................... 22 Conditioned place preference ................................................................................. 23 Drug Discrimination .................................................................................................................... 24 Background ....................................................................................................................... 24 iii Table of Contents—Continued Quantal versus graded dose-response effects .................................................................... 27 MDPV and 4-MMC in drug discrimination ..................................................................... 27 Current Research Objective ......................................................................................................... 29 METHODS ............................................................................................................................................. 29 Subjects ........................................................................................................................................ 29 Apparatus ..................................................................................................................................... 29 Drugs............................................................................................................................................ 30 Operant Training Procedures ....................................................................................................... 30 Magazine training.............................................................................................................. 30 Lever press training ........................................................................................................... 30 Errorless (single lever) training
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