The Transitional States of Drug Addiction in Rhesus Monkeys Open Access

Henry, Porche' Kirkland (2009)

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Long-term cocaine use leads to a compulsive pattern of drug intake and an increased propensity to relapse during periods of abstinence. Such compulsive, escalated use has been associated with a number of physiological changes within the dopamine system. This project was designed to identify endpoints associated with the transition from recreational use to periods of extensive drug use and withdrawal by characterizing changes in behavior, neurochemistry, and functional brain activation as a function of drug history. Rhesus monkeys trained to self-administer cocaine were provided limited cocaine access restricting total daily intake. After several weeks under the limited access condition, an extended access condition was added during which subjects had the opportunity to escalate daily drug intake. Bimonthly reinstatement experiments conducted during the periods of limited and extended access determined changes in vulnerability to reinstate extinguished drug seeking behavior as cocaine exposure increased over time. Data from reinstatement tests were then complemented with direct and indirect measures of dopamine system function with in vivo microdialysis, acoustic startle, and FDG-PET imaging. Sensitivity to psychostimulants on enhancing extracellular dopamine in the striatum, altering the behavioral-stimulant response to acoustic startle, and modulating the pattern of cortical brain activation were also determined after each access period and following a period of drug withdrawal. Extended access to cocaine self-administration lead to increased cocaine intake but did not result in escalation. Surprisingly, there was no effect of drug history on cocaine- induced reinstatement or sensitivity to psychostimulants on startle amplitude. There were, however, diminished drug-induced increases in striatal dopamine as measured with dialysis and enhanced brain activity throughout the frontal cortex and striatum over time. Collectively, these studies created a neurochemical profile of cocaine's effect on the brain of rhesus monkeys with a prolonged history of drug self- administration. Conclusions made from this project are potentially a step towards developing better animal models in which to evaluate prospective pharmacotherapies.

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Table of Contents

Table of Contents List of Figures List of Tables Chapter I: Introduction 1 Chapter II: Background 7 A. Dopamine and Cocaine Reinforcement 7 B. Self-Administration 18 -- Reinstatement as a Model of Relapse 19 C. Direct Measures of Dopamine by in vivo Microdialysis 21 D. The Acoustic Startle Response 23 E. Brain Energy Metabolism 27 F. Summary 31 Chapter III: Cocaine-induced reinstatement during limited and extended drug access conditions in rhesus monkeys 32 A. Introduction 32 B. Materials and Methods 34 C. Results 40 D. Discussion 49 Chapter IV: Effects of cocaine self-administration history on in vivo striatal dopamine neurochemistry and acoustic startle in rhesus monkeys 53 A. Introduction 53 B. Materials and Methods 56 C. Results 68 D. Discussion 85 Chapter V: Acute brain metabolic effects of cocaine in rhesus monkeys with a history of cocaine self-administration 91 A. Introduction 91 B. Materials and Methods 94 C. Results 99 D. Discussion 107 Chapter VI: Conclusions 113 -- Future Directions 121 References 124

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