COCAINE SELF-ADMINISTRATION IN RHESUS MONKEYS: EFFECTS ON NEUROBIOLOGY AND COGNITION AND EVALUATION OF COGNITIVE ENHANCEMENT FOR ADDICTION TREATMENT BY ROBERT W. GOULD A Dissertation Submitted to the Graduate Faculty of WAKE FOREST UNIVERSITY GRADUATE SCHOOL OF ARTS AND SCIENCES in Partial Fulfillment of the Requirements for the Degree of DOCTOR OF PHILOSOPHY Physiology and Pharmacology DECEMBER 2011 Winston-Salem, North Carolina Approved By: Michael A. Nader, Ph.D., Advisor Examining Committee: Beth A. Reboussin, Ph.D., Chairperson Paul W. Czoty, Ph.D. Kristen G. Jordan, Ph.D. Michelle M. Nicolle, Ph.D. ACKNOWLEDGEMENTS I could not have reached this milestone in my scientific career without the support and guidance from a large group of people. I credit Dr. Barbara Lom for stimulating my interest in science and Laura Majersky, Heather Green, and Dr. Kathleen Grant for giving me my first employment opportunity and the training to safely and efficiently conduct nonhuman primate studies. I appreciate the unwavering love and support from my family. I hope I have maintained most of the positive qualities they instilled in me. My father once told me that keys to success included surrounding oneself with smart people, working ~60 hours/week, and becoming irreplaceable by learning multiple skill sets. Based on that advice I surrounded myself with a wonderful dissertation committee. Thanks to Drs. Paul Czoty, Kristen Jordan, Michelle Nicole, Beth Reboussin and Michael Nader for their help, support, and guidance. A special thanks to my mentor, Dr. Nader, the hardest working man I know besides my own father. Although Dr. Nader frequently complains that his students are “working him to the bone”, he set the standard for our efforts. Our success is a reflection of his drive, thoughtful mentoring and his always-present, open-door policy that facilitated our productivity at the expense of his own. Dr. Nader gave me the opportunity to explore my own studies and encouraged a collaborative approach to research. I appreciate these collaborations and the experience I gained working with Drs. Robert Kraft, Donald Gage, and James Daunais. I would be remiss without acknowledging all prior and current lab members and animals resources personnel that I have been lucky enough to work with and learn from. ii Thanks to Michael Coller, Susan Martelle and Whitney Wilson for all of their assistance. I owe a very special "thank you” to Tonya Calhoun and Michelle Icenhower. Together, we complained of the occasional forgetful nature of students that left more work for technicians. When I matriculated, I too resembled a “forgetful student” at times, and yet received nothing but complete support from them both. Also, I appreciate all of the time and effort Susan Nader has put forth, both directly and indirectly to facilitate my progress and improve the laboratory as a whole. I wish to thank Drs. Jennifer Martelle and Matthew Banks. While pursuing their own graduate studies, each unknowingly set an example through their hard work, dedication and friendship. I can only hope some of their influence has been passed on through me to other matriculating students. Thanks to Dr. Lindsey Hamilton, Brandi Blaylock, Rob Brutcher and Sarah Kromrey for their friendship, help and support, and often-needed cathartic chiding and laughter. Lastly, I owe my deepest love and gratitude to my beautiful wife Kelly. She has endured professional science talks during preparation and casual science talk among friends, ad nauseam. She has gone to bed alone too many nights and awakened alone on too many weekends. She is the first to support me in times of frustration, first to celebrate at each milestone, and first to remind me that I too can be, and often am wrong. Thank you for your patience, understanding and support while I worked towards a “real job”. This research was funded by DA12460, DA10584 and DA06630 from the National Institute on Drug Abuse. iii TABLE OF CONTENTS PAGE LIST OF ABBREVIATIONS v LIST OF TABLES vii LIST OF FIGURES viii ABSTRACT x CHAPTER I INTRODUCTION: PRECLINICAL MODELS AND CLINICAL STUDIES OF COCAINE ABUSE: INSIGHTS FOR FUTURE PHARMACOTHERAPY DEVELOPMENT 1 Portions of this Chapter were published: Gould RW, Porrino LJ, Nader MA. Nonhuman primate models of addiction and PET imaging: Dopamine system dysregulation. In JW Dalley, CS Carter (eds), “Brain Imaging in Behavioral Neuroscience”, Springer, Heidelberg, Germany, in press. II EFFECTS OF COCAINE SELF-ADMINISTRATION AND ABSTINENCE ON WORKING MEMORY IN RHESUS MONKEYS 108 III EFFECTS OF COCAINE SELF-ADMINISTRATION ON SET SHIFTING BEHAVIOR AND NEURAL ACTIVITY IN RHESUS MONKEYS 140 Submitted to Cerebral Cortex August 23, 2011 IV EFFECTS OF NICOTINIC ACETYLCHOLINE RECEPTOR STIMULATION ON COGNITION IN RHESUS MONKEYS WITH A CHRONIC COCAINE SELF-ADMINISTRATION HISTORY 179 Submitted to Neuropsychopharmacology October, 2011 V EFFECTS OF VARENICLINE ON THE REINFORCING AND DISCRIMINATIVE STIMULUS EFFECTS OF COCAINE IN RHESUS MONKEYS 221 Accepted for Publication in Journal of Pharmacology and Experimental Therapeutics August 17, 2011 VI DISCUSSION 257 APPENDIX 299 SCHOLASTIC VITAE 300 iv LIST OF ABBREVIATIONS 2DG [14C]-2-deoxyglucose 5-CSRTT 5-choice serial reaction time task 5-HT serotonin ACC anterior cingulate cortex ACh acetylcholine AChR acetylcholine receptor AD Alzheimer’s Disease Am amydgala b.i.d. twice a day BL baseline BP breakpoint Ca2+ calcium CANTAB Cambridge Neuropsychological Test Automated Battery Cb cerebellum CBT cognitive behavioral therapy Cd caudate nucleus CD compound discrimination CM contingency management CNS central nervous system COMT catechol-O-methyltransferase CPP conditioned place preference CRA community reinforcement approach CS conditioned stimulus D1 dopamine D1-like receptor superfamily D1 dopamine D1 receptor subtype D2 dopamine D2-like receptor superfamily D2 dopamine D2 receptor subtype D3 dopamine D3 receptor subtype D4 dopamine D4 receptor subtype D5 dopamine D5 receptor subtype DA dopamine DAT dopamine uptake transporter DD drug discrimination dlPFC dorsolateral prefrontal cortex DMS delay match-to-sample DRL differential reinforcement of low rates DRO differential reinforcement of other ED extradimensional shift ED50 interpolated effective dose that engenders 50% response FDG [18F]-2-deoxy-2-flouro-D-glucose FI fixed-interval fMRI functional magnetic resonance imaging FR fixed-ratio GABA gamma-Aminobutyric acid v ID/ED intra/exta-dimensional shift IGT Iowa Gambling Task i.m. intra-muscular i.p. intraperitoneal i.v. intravenous MCC mid-cingulate gyrus Mec mecamylamine hydrochloride MET motivational enhancement therapy mPFC medial prefrontal cortex MR magnetic resonance MRglu metabolic rates of glucose utilization NE norepinephrine NET norepinephrine uptake transporter NHP nonhuman primate Nic nicotine bitartrate nAChR nicotinic acetylcholine receptor orbPFC orbital prefrontal cortex PCC posterior cingulate cortex PD Parkinson’s disease PET positron emission tomography PFC prefrontal cortex PNU-282987 N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide hydrochloride PR progressive-ratio Pt putamen RVIP Rapid Visual Information Processing task S+ stimulus signalling reinforcement S- stimulus signalling trial termination, lack of reinforcement SA self-administration SAT sustained attention task SD simple discrimination (Chapter I, IV); standard deviation (Chapter II) SEM standard error of the mean SERT serotonin uptake transporter s.i.d. once a day SPM statistical parametric map SR reinforcer SSRI selective serotonin reuptake inhibitor SSRT stop-signal reaction test STG superior temporal gyrus Th thalamus TO time-out Var varenicline dihydrochloride VMAT vesicular monoamine transporter VTA ventral tegmental area WGTA Wisconsin General Testing Apparatus WO washout vi LIST OF TABLES PAGE CHAPTER II Table I. Daily intake and response rates (RR; responses/sec) during cocaine or food self-administration 120 Table II. Individual percent accuracy across increasing delay values and individualized delays for baseline delay-effect curves 123 CHAPTER III Table I. Subject information and drug history 145 Table II. Task performance prior to and during FDG incorporation 157 Table III. Differences in relative glucose utilization between cocaine-naive monkeys and cocaine-experienced monkeys (n=4/group) 158 Table IV. Glucose utilization between a baseline motor task (BL) and an extradimensional shift (EDS) in cocaine-naive monkeys and cocaine- experienced monkeys (n=4/group) 160 CHAPTER IV Table I. Individual and mean (±SEM) ratios of [11C]-nicotine uptake for each region of analysis 193 Table II. Individual baseline parameters that produced similar delay-dependent effects on DMS performance; dist., distracter images 195 Table III. Maximal effect (and dose) of nicotine (Nic) varenicline (Var), or PNU- 282987 (PNU) administration on DMS performance 199 CHAPTER V Table I. Effects of haloperidol on the discriminative stimulus effects of cocaine 244 CHAPTER VI Table I. Individual baseline (BL) DVRs for DA D2-like receptor availability and percent reductions from BL following 6 months of cocaine SA and 30 days of abstinence 263 vii LIST OF FIGURES PAGE CHAPTER II Figure 1. Group delay-effect curves (mean ± SEM) for cocaine-naive (n=4, except t=90, 120, n=3) and monkeys with a cocaine self-administration history (n=3, except t=120, n=1) 122 Figure 2. Effects of high-dose cocaine and abstinence on delayed match-to-sample performance (group data) 125 Figure 3. Effects of high-dose cocaine and abstinence