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The Effect of a Neuroactive Steroid Analog and An THE EFFECT OF A NEUROACTIVE STEROID ANALOG AND AN EXTRASYNAPTIC GABAA RECEPTOR AGONIST ON ETHANOL CONSUMPTION AND SEEKING IN MICE By Marcia Jean Ramaker A DISSERTATION Presented to the Department of Behavioral Neuroscience and Oregon Health & Science University School of Medicine In partial fulfillment of the requirements for the degree of Doctor of Philosophy February 2014 School of Medicine Oregon Health & Science University _______________________________________________________________ CERTIFICATE OF APPROVAL ___________________________________ This is to certify that the Ph.D. dissertation of Marcia J. Ramaker has been approved ______________________________________ Deborah Finn, Mentor ______________________________________ Andrey Ryabinin, Chair ______________________________________ Gregory Mark, Member ______________________________________ Kathleen Grant, Member ______________________________________ Amy Eshleman, Member ______________________________________ Charles Meshul, Member TABLE OF CONTENTS LIST OF FIGURES………………………………………………………………………………iv LIST OF TABLES………………………………………………………………………………..vi LIST OF ABBREVIATIONS ........................................................................................... vii ACKNOWLEDGEMENTS ................................................................................................ x OVERALL ABSTRACT…………………………………………………….……………..……xiii CHAPTER 1: GENERAL INTRODUCTION………………...…………………………...……1 GABAA receptor: subunits and binding sites ................................................................... 2 The GABAA receptor and neuroactive steroids ............................................................... 4 Steroidogenesis .............................................................................................................. 6 The GABA A receptor and ethanol ................................................................................... 8 The GABAA receptor, ALLO, and ethanol ....................................................................... 9 ALLO and ethanol intake ...............................................................................................12 Extrasynaptic GABAA receptors: ethanol and ALLO ......................................................14 Region-specific GABAA receptor manipulations and ethanol intake ...............................18 Reward Circuitry: NAc ...................................................................................................19 Goals of the Dissertation ...............................................................................................24 CHAPTER 2: ALTERATION OF 24-HOUR ETHANOL DRINKING IN MICE VIA MODULATION OF THE GABAA RECEPTOR WITH GANAXOLONE, FINASTERIDE, AND THIP .....................................................................................................................33 Abstract .........................................................................................................................34 Introduction ...................................................................................................................35 Materials and Methods ..................................................................................................38 Results ..........................................................................................................................43 Discussion .....................................................................................................................50 CHAPTER 3: EFFECT OF GANAXOLONE AND THIP ON OPERANT AND LIMITED- ACCESS ETHANOL SELF-ADMINISTRATION .............................................................69 i Abstract .........................................................................................................................70 Introduction ...................................................................................................................70 Materials and Methods ..................................................................................................75 Results ..........................................................................................................................82 Discussion .....................................................................................................................88 CHAPTER 4: EFFECT OF NUCLEUS ACCUMBENS SHELL INFUSIONS OF GANAXOLONE OR THIP ON ETHANOL INTAKE ...................................................... 106 Abstract ....................................................................................................................... 107 Introduction ................................................................................................................. 107 Materials and Methods ................................................................................................ 110 Results ........................................................................................................................ 118 Discussion ................................................................................................................... 125 CHAPTER 5: GANAXOLONE, BUT NOT THIP, REINSTATES ETHANOL SEEKING IN MICE ........................................................................................................................... 143 Abstract ....................................................................................................................... 144 Introduction ................................................................................................................. 145 Methods ...................................................................................................................... 147 Results ........................................................................................................................ 152 Discussion ................................................................................................................... 154 CHAPTER 6: GENERAL DISCUSSION ...................................................................... 164 Initial hypothesis .......................................................................................................... 164 Summary of findings .................................................................................................... 164 General interpretations ................................................................................................ 166 Revised hypothesis: ethanol seeking ........................................................................... 168 Revised Hypothesis: ethanol consumption .................................................................. 170 Proposed mechanism .................................................................................................. 171 Proposed cirtcuitry ....................................................................................................... 173 ii Potential brain areas underlying GAN or THIP effects ................................................. 177 Alternative hypotheses ................................................................................................ 180 Order effects with GAN ................................................................................................ 184 Order effects with THIP ............................................................................................... 186 Plasticity following chronic ethanol exposure ............................................................... 188 Dose of GAN ............................................................................................................... 190 Doses of THIP ............................................................................................................. 192 Sex differences ............................................................................................................ 193 Locomotor and other off-target effects of THIP or GAN ............................................... 194 Relevance to humans .................................................................................................. 195 Final conclusions ......................................................................................................... 196 APPENDIX: Pilot experiment testing the effect of THIP on ethanol intake following ethanol abstinence (i.e., the alcohol deprivation effect) ............................................... 200 REFERENCES ............................................................................................................ 211 iii LIST OF FIGURES Figure 1.1. The pentameric GABAA receptor showing binding sites of GABAA receptor- acting molecules .............................................................................................................29 Figure 1.2. Steroidogenesis pathway ..............................................................................30 Figure 1.3. Molecular structure of allopregnanolone (ALLO) and ganaxolone (GAN) ......31 Figure 1.4. Simplified reward circuitry showing the major NAc inputs and outputs ..........32 Figure 2.1. 10E lick correlation and hourly pattern .........................................................62 Figure 2.2. Effects of GAN on the first 6 hours of ethanol access. ..................................63 Figure 2.3. Effects of FIN on the first 6 hours of ethanol access .....................................64 Figure 2.4. Effects of THIP on the first 6 hours of ethanol access ..................................65 Figure 3.1. Effect of
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