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University of Cincinnati UNIVERSITY OF CINCINNATI _____________ , 20 _____ I,______________________________________________, hereby submit this as part of the requirements for the degree of: ________________________________________________ in: ________________________________________________ It is entitled: ________________________________________________ ________________________________________________ ________________________________________________ ________________________________________________ Approved by: ________________________ ________________________ ________________________ ________________________ ________________________ Differential Involvement of Opioid Receptors in Regulating the Behavioral Response to Amphetamine in C57BL/6 Mice. A dissertation submitted to the Division of Research and Advanced Studies of the University of Cincinnati in partial fulfillment of the requirements for the degree of DOCTORATE OF PHILOSOPHY (Ph.D.) in the Department of Cell Biology, Neurobiology, and Anatomy of the College of Medicine 2002 by Jonathan W. Yates B.A., Knox College, 1991 Committee Chair: Lei Yu Abstract: Drug addiction is recognized as a serious brain disease and with the rapid expansion in neuroscience research over the past few decades, great progress has been made in understanding the causes and effects of drug addiction and its relevance to more basic components of human behavior. It is now accepted that drugs of abuse (DOA) act on the mesolimbic dopamine (DA) brain reward system to mimic the rewards induced by more ‘natural’ stimuli such as food and sex. Acute administrations of DOA, particularly the psychostimulant amphetamine (AMPH), and the opiate heroin, lead to increases in extracellular levels of the neurotransmitter dopamine in regions comprising the brain reward system, including the nucleus accumbens (NAc), the ventral tegmental area (VTA), the striatum, and the dorsal caudate (DC). Changes in DA levels contribute to both the rewarding properties of DOA, as well as behavioral aspects of their use. As knowledge of the molecular and behavioral effects of DOA has advanced, evidence has accumulated that opioids not only share similar rewarding properties as psychostimulants, but that the endogenous opioid system can directly modulate the mesolimbic dopaminergic system as well. However, the individual contributions of the three opioid receptors subtypes (µ, κ, and δ) in modulating the brain reward system are still unclear. In an attempt to investigate this, we developed an animal model of acute amphetamine (AMPH) –induced behaviors and studied the effect of antagonizing the individual opioid receptors (ORs) on these behaviors. Using the induction of hyperlocomotion following a low dose (2mg/kg) of AMPH as a behavioral correlate of DA levels, we found that antagonizing the δOR significantly attenuated behavior, antagonism of κORs failed to effect behavior, and antagonism of µORs had a slight, but non-significant, augmentation of DA-dependent hyperlocomotion. In contrast, utilizing the induction of stereotypic behaviors with a high dose (12mg/kg) of AMPH as our behavioral correlate, antagonism of all three ORs significantly attenuated DA-dependent stereotypy. It is assumed that these OR-dependent effects are mediated through differential regulation of target neurons within the mesolimbic reward system and indicate that the endogenous opioid system can regulate behavioral responses to rewarding stimuli. Table of Contents Chapter One _____________________________________________4 Introduction _____________________________________________________________________ 4 1.1. Introduction: _______________________________________________________________________5 1.2. Dopamine and the Brain Reward System ________________________________________________6 1.3. The Opioid System and Receptors: ____________________________________________________10 1.4. The Dopamine System and Receptors: _________________________________________________12 1.5. Opioid System Regulation of DA System:_______________________________________________13 1.6. The Goals for this Project: ___________________________________________________________20 Chapter Two ____________________________________________23 Evaluation of Amphetamine-induced Behavior in C57BL/6 Mice_________________________ 23 2.1. Introduction: ______________________________________________________________________24 2.2. Materials and Methods: _____________________________________________________________27 Subjects: ____________________________________________________________________________27 Locomotor Activity:.___________________________________________________________________27 Drugs:. _____________________________________________________________________________28 Data Analysis: _______________________________________________________________________29 2.3. Results:___________________________________________________________________________29 2.3-A: Amphetamine-induced Locomotion:_________________________________________________29 2.3-B: Amphetamine-induced Stereotypy:__________________________________________________33 2.3-C: Comparison of Selected AMPH doses: _______________________________________________36 2.3-D: Time Course Evaluation: _________________________________________________________45 2.4. Discussion: ________________________________________________________________________51 Chapter Three ___________________________________________56 Differential Involvement of Opioid Receptors in Amphetamine-induced Behaviors in C57BL/6 Mice ___________________________________________________________________________ 56 3.1. Introduction: ______________________________________________________________________57 3.2. Materials and Methods: _____________________________________________________________63 Subjects: ____________________________________________________________________________63 Locomotor Activity: ___________________________________________________________________63 Drugs: _____________________________________________________________________________64 Data Analysis: _______________________________________________________________________65 3.3. Results: ___________________________________________________________________________65 3-3-1: Antagonist Dose Responses:_______________________________________________________65 3-3-2: Antagonist Pretreatment + Amphetamine:____________________________________________71 Locomotion Results: ____________________________________________________________________74 3-3-2A: Naloxone + AMPH: ____________________________________________________________74 3-3-2B: β-FNA + AMPH: ______________________________________________________________77 3-3-2C: Naltrindole + AMPH: __________________________________________________________80 3-3-2D: nor BNI + AMPH:_____________________________________________________________83 Stereotypy Results: _____________________________________________________________________88 1 3-3-3 Stereotypy: _____________________________________________________________________88 3.4. Discussion: ________________________________________________________________________93 Chapter Four ___________________________________________104 Discussion _____________________________________________________________________ 104 4.1. Discussion: _______________________________________________________________________105 4.2. Development of Animal Model: ______________________________________________________107 4.3. Analysis of Amphetamine Response in C57 Mice: _______________________________________109 4.4. Amphetamine-induced Locomotion and Stereotypy: _____________________________________111 4.5. Identification of Time Interval for Analysis: ____________________________________________112 4.6. Effects of Opioid Antagonists on Basal Activity in C57 Mice: ______________________________115 4.7. Opioid Antagonists and Amphetamine-induced Behaviors: _______________________________118 4.8. Mechanisms for Opioid Receptor Regulation of Amphetamine-induced Behaviors: ___________120 4.9. Summary: ________________________________________________________________________126 4.10. Future Directions: ________________________________________________________________128 Chapter Five ___________________________________________130 Bibliography ___________________________________________________________________ 130 2 Table of Figures CHAPTER 1 FIGURE 1-1 ------------------------------------------------------------------------------------------------------------------------ 08 CHAPTER 2 FIGURE 2-1------------------------------------------------------------------------------------------------------------------------ 32 FIGURE 2-2------------------------------------------------------------------------------------------------------------------------ 35 FIGURE 2-3A ---------------------------------------------------------------------------------------------------------------------38 FIGURE 2-3B -----------------------------------------------------------------------------------------------------------------------35 FIGURE 2-3C -----------------------------------------------------------------------------------------------------------------------37 FIGURE 2-4------------------------------------------------------------------------------------------------------------------------ 47 FIGURE 2-5------------------------------------------------------------------------------------------------------------------------ 50 CHAPTER 3 FIGURE 3-1 -------------------------------------------------------------------------------------------------------------------------58
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