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A Mouse Model of Toluene Abstinence-Induced Pathology Sean Callan Wayne State University

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A Mouse Model of Toluene Abstinence-Induced Pathology Sean Callan Wayne State University Wayne State University Wayne State University Dissertations 1-1-2016 A Mouse Model Of Toluene Abstinence-Induced Pathology Sean Callan Wayne State University, Follow this and additional works at: http://digitalcommons.wayne.edu/oa_dissertations Part of the Biological Psychology Commons Recommended Citation Callan, Sean, "A Mouse Model Of Toluene Abstinence-Induced Pathology" (2016). Wayne State University Dissertations. 1628. http://digitalcommons.wayne.edu/oa_dissertations/1628 This Open Access Dissertation is brought to you for free and open access by DigitalCommons@WayneState. It has been accepted for inclusion in Wayne State University Dissertations by an authorized administrator of DigitalCommons@WayneState. A MOUSE MODEL OF TOLUENE ABSTINENCE-INDUCED PATHOLOGY by SEAN P. CALLAN DISSERTATION Submitted to the Graduate School of Wayne State University, Detroit, Michigan in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY 2016 MAJOR: PSYCHOLOGY (Behavioral and Cognitive Neuroscience) Approved By: ________________________________________ Advisor Date ________________________________________ ________________________________________ ________________________________________ DEDICATION To my wife Jade for putting up with all my insanity. ii ACKNOWLEDGMENTS This work would not be possible without the help and guidance of my advisor, Dr. Scott Bowen and the timely help of Cameron Davidson and Joseph Lombardo. Finally, I would like to express my gratitude and thanks to my thesis committee, Dr. John Hannigan, Dr. Shane Perrine, and Dr. Susanne Brummelte. iii TABLE OF CONTENTS Dedication ....................................................................................................................................... ii Acknowledgments ......................................................................................................................... iii List of Tables ................................................................................................................................ vii List of Figures .............................................................................................................................. viii Chapter 1 Introduction .....................................................................................................................1 1.1 Relevant Terminology ...................................................................................................3 1.2 Toluene .........................................................................................................................4 1.3 Toluene Epidemiology ..................................................................................................6 1.4 Pharmacodynamic properties of toluene .......................................................................8 Chapter 2 Inhalant Withdrawal ..................................................................................................... 12 2.1 Toward an animal model of toluene withdrawal ........................................................16 2.2 Research Questions and Hypotheses ..........................................................................21 Chapter 3 “Methods” ....................................................................................................................23 3.1 Subjects ....................................................................................................................... 23 3.2 Exposure Apparatus .................................................................................................... 26 3.3 Acute Toluene Abstinence .......................................................................................... 27 3.4 Specific Methods ........................................................................................................28 3.4.1 H1: Handling-induced seizures in mice ....................................................................28 3.4.2 H2 and H3: Pentylenetetrazol-induced convulsions ................................................ 30 3.4.3 H4: Elevated Plus Maze test .................................................................................... 31 3.4.4 H5: Open Field Test ..................................................................................................32 3.4.5 H6: Light/Dark Box ..................................................................................................33 iv 3.4.6 H7: Marble Burying Test ..........................................................................................33 3.4.7 H8: Toluene Re-exposure .........................................................................................34 3.5 Data Analysis ...............................................................................................................35 Chapter 4: Results ..........................................................................................................................36 4.1 24 hour Toluene exposure: Stability ...........................................................................36 4.2 Weight Changes: 24 hour exposure ............................................................................36 4.3 Recovery from weight loss .........................................................................................37 4.4 H1: Handling-induced seizure activity .......................................................................38 4.5 H2: 48 mg/kg PTZ-induced seizure activity ................................................................40 4.6 H3 and H8: 42 mg/kg PTZ-induced seizure activity .................................................43 4.7 H4: Elevated Plus Maze ..............................................................................................46 4.8 H5: Light/Dark Box ....................................................................................................48 4.9 H6: Open Field Test .................................................................................................... 53 4.10 H7: Marble Burying Test ..........................................................................................54 Chapter 5: Discussion ...................................................................................................................57 5.1 Toluene withdrawal decreases seizure threshold in mice ............................................57 5.2 Toluene withdrawal leads to an anxiety-like response in mice: EPM .........................63 5.3 Toluene withdrawal leads to an anxiety-like response in mice: MBT, LDB, OFT ...............................................................................................................65 5.4 Overall conclusions and future directions ................................................................... 71 References .....................................................................................................................................74 Abstract ........................................................................................................................................ 93 Autobiographical Statement .......................................................................................................... 95 LIST OF TABLES v Table 1: Animal Numbers ..............................................................................................................23 Table 2: List of behaviors scored as seizure activity .....................................................................31 LIST OF FIGURES vi Figure 1: Pilot Data ........................................................................................................................19 Figure 2: Schematic of dynamic exposure system ........................................................................27 Figure 3: An example 24 hour plot of toluene vapor concentration .............................................36 Figure 4: 24 hour weight loss ........................................................................................................37 Figure 5: Weight recovery ............................................................................................................38 Figure 6: Handling induced seizures .............................................................................................39 Figure 7: Individual plots of Handling-induced seizures ..............................................................40 Figure 8: Seizure response to 48 mg/kg PTZ.................................................................................41 Figure 9: 48 mg/kg PTZ-induced seizures symptoms scored .......................................................42 Figure 10: Seizure response to 42 mg/kg PTZ ..............................................................................44 Figure 11: 42 mg/kg PTZ-induced seizures clonic symptoms scored ...........................................45 Figure 12: 42 mg/kg PTZ-induced seizures tonic symptoms scored .............................................45 Figure 13: Anxiolytic Effects of 2 g/kg ETOH in EPM ...............................................................46 Figure 14: Anxiety-like effects of 24 hour toluene abstinence in EPM .......................................47 Figure 15 Anxiety-like effects of 72 hour toluene abstinence in EPM .........................................47 Figure 16: Anxiolytic effects of acute toluene exposure in EPM ..................................................48 Figure 17: Anxiolytic effects of 2 g/kg ETOH in LDB .................................................................49
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