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I the EFFECTS of NEUROACTIVE STEROIDS on ACUTE ETHANOL

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I the EFFECTS of NEUROACTIVE STEROIDS on ACUTE ETHANOL THE EFFECTS OF NEUROACTIVE STEROIDS ON ACUTE ETHANOL WITHDRAWAL IN MICE by Katherine R. Kaufman A DISSERTATION Presented to the Department of Behavioral Neuroscine and the Oregon Health & Science University School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy December 2009 i School of Medicine Oregon Health & Science University ___________________________________ CERTIFICATE OF APPROVAL ___________________________________ This is certify that the Ph.D. dissertation of Katherine Kaufman has been approved ______________________________________ Deborah A. Finn, Mentor ______________________________________ Gregory P. Mark, Member ______________________________________ Kathleen A. Grant, Member ______________________________________ Kristine M. Wiren, Member ______________________________________ Charles E. Roselli, Member ii TABLE OF CONTENTS LIST OF FIGURES ...............................................................................................v LIST OF TABLES ............................................................................................... vi LIST OF ABBREVIATIONS ............................................................................ vii ACKNOWLEDGMENTS ................................................................................... ix ABSTRACT ......................................................................................................... xii CHAPTER 1. General Introduction ....................................................................1 Alcohol Dependence and Withdrawal: Definitions and Clinical Significance ..........................................................1 Neuroactive Steroids ...................................................................................4 Behavioral Properties of the 5α-Reduced Neuroactive Steroids .................7 Steroids and Seizure Susceptibility ..............................................................9 Ethanol and Neuroactive Steroids .............................................................13 Animal Models of Ethanol Withdrawal-Related Convulsive Behavior......15 The Role of the Hippocampus ....................................................................18 The GABAA Receptor .................................................................................19 Hypothesis and Goals of the Dissertation .................................................22 CHAPTER 2: THE IMPACT OF GONADECTOMY AND ADRENALECTOMY ON ACUTE WITHDRAWAL SEVERITY IN MALE AND FEMALE C57BL/6J AND DBA/2J MICE FOLLOWING A SINGLE HIGH DOSE OF ETHANOL............................................................................................................28 Abstract ......................................................................................................29 Introduction................................................................................................31 iii Materials and Methods .............................................................................34 Results ........................................................................................................40 Discussion ..................................................................................................45 CHAPTER 3: REPLACEMENT WITH GABAERGIC STEROID PRECURSORS RESTORES THE ACUTE ETHANOL WITHDRAWAL PROFILE IN ADX/GDX MICE .....................................................................................................................59 Abstract ......................................................................................................60 Introduction................................................................................................62 Materials and Methods ..............................................................................66 Results ........................................................................................................71 Discussion ..................................................................................................75 CHAPTER 4: EFFECTS OF STEROID ADMINISTRATION PRIOR TO ACUTE ETHANOL WITHDRAWAL ON mRNA FOR GABAA RECEPTOR SUBUNITS AND STAR PROTEIN IN INTACT AND ADRENALECTOMIZED/GONADECTOMIZED DBA/2J MALE AND FEMALE MICE .....................................................................................................................86 Abstract ......................................................................................................87 Introduction................................................................................................89 Materials and Methods ..............................................................................92 Results ........................................................................................................95 Discussion ................................................................................................100 CHAPTER 5: GENERAL DISCUSSION .......................................................117 A role for Neuroactive Steroids during Ethanol Withdrawal ..............................117 The Role of GABAA Receptor Subunits in Acute Ethanol Withdrawal ................120 Future Directions .................................................................................................122 Overall implications.............................................................................................126 REFRENCES .....................................................................................................128 iv LIST OF FIGURES Figure 1.1. Biosynthesis of neuroactive steroids ...........................................26 Figure 2.1. The effect of surgical status on acute ethanol (EtOH) withdrawal severity in male and female C57BL ⁄ 6J (B6) and DBA⁄ 2J (D2) mice, measured by hourly handling- induced convulsions (HICs). ............................................................................54 Figure 2.2 Surgical status significantly alters acute ethanol (EtOH) withdrawal severity, measured by area under the curve (AUC). .......................................................55 Figure 2.3. Surgical status significantly affects peak withdrawal scores in male mice, but not in female mice. ...........................................................................................56 Figure 2.4. Surgical status has no significant effect on EtOH metabolism. ...57 Figure 3.1. The effects of steroid replacement on acute ethanol (EtOH) withdrawal severity in male DBA⁄2J mice, measured by hourly handling-induced convulsions (HICs). .........................................................................................81 Figure 3.2. The effects of steroid replacement on acute ethanol withdrawal severity in female DBA⁄2J mice, measured by hourly HICs. ............................................82 Figure 3.3. The effect of steroid replacement on acute ethanol withdrawal severity in DBA⁄2J mice, measured by AUC. .................................................................83 Figure 3.4. Two doses of 50 mg/kg finasteride reliably decreased ALLO production over the 24 hour withdrawal period. ........................................................................84 Figure 4.1. The effects of steroid administration during acute EtOH withdrawal on expression of the GABAA receptor α1 subunit mRNA. ................................110 Figure 4.2. The effects of steroid administration during acute EtOH withdrawal on expression of StAR protein mRNA. ............................................................111 v LIST OF TABLES Table 1.1 Handling induced convulsion (HICs) scoring. ......................................27 Table 2.1. Clearance parameters ...........................................................................58 Table 3.1. Treatments administered and references supporting the doses chosen...........................................................................................................85 Table 4.1. Gene expression changes in vehicle treated mice: Effects of surgery and sex ....................................................................................112 Table 4.2. Gene expression changes in female ADX/GDX mice: Effects of steroid pretreatments versus vehicle ................................................................................113 Table 4.3. Gene expression changes in female SHAM mice: Effects of steroid pretreatments versus vehicle. ...............................................................................114 Table 4.4. Gene expression changes in male ADX/GDX Mice: Effects of steroid pretreatment versus vehicle..................................................................................115 Table 4.5. Gene expression changes in male SHAM mice: Effects of steroid pretreatment versus vehicle .......................................................................................................116 vi LIST OF ABBREVIATIONS ADX - adrenalectomy ALLO - 3α, 5α tetrahydroprogesterone; allopregnanolone ANOVA - analysis of variance AUC - area under the curve B6 – C57BL/6J BEC - blood ethanol concentration CNS - central nervous system CORT - corticosterone D2 - DBA/2J DHEA - Dihydroepiandrosterone DHEAS- Dihydroepiandosterone sulfate 5α-DHP - 5α dihydroprogesterone DOC - deoxycorticosterone EtOH - ethanol FIN - finasteride GABAA- γ-aminobutyric acidA GAN - ganaxolone GDX - gonadectomy HIC – handling-induced convulsion HPA - hypothalamic-pituitary-adrenal 5-HT- serotonin vii IP - intraperitoneal KO – knock out NAS - neuroactive steroid NMDA - N-methyl-D-aspartate
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