Serotonin 5-HT2C Receptor Modulation of Compulsive and Addictive Behavior in Female Rhesus Macaques 公开

Perez Diaz, Maylen (Fall 2017)

Permanent URL: https://etd.library.emory.edu/concern/etds/t148fh13t?locale=zh
Published

Abstract

Addiction is a significant public health issue, yet there are limited FDA-approved treatments for certain addictive disorders and none for addiction in general. Identifying the core behavioral and neurochemical processes contributing to an addictive phenotype can inform the development of novel therapeutics to treat multiple addictions. Compulsivity has been highly implicated in the etiology of addiction and reported to be higher among addicted individuals compared to controls. Despite this evidence, the effects of long-term engagement in addictive behaviors on compulsivity have not been tested. Although studies provide evidence that serotonin 5-HT2C receptors are involved in the expression of both compulsive and addictive behaviors, the extent to which these behaviors are regulated in parallel is unknown and the exact effects of 5-HT2C receptors on compulsivity remain unclear. Therefore, the following set of studies employed two types of reinforcers, a high caloric diet (HCD) and methamphetamine (METH), to investigate the effects of long-term intake of these reinforcers on general compulsive behavior in female rhesus macaques. In addition, the present study evaluated the effects of a 5-HT2C receptor agonist, WAY163909 on baseline compulsivity, compulsivity following long-term reinforcer intake, drug intake and drug-seeking of METH, and intake of two different diets. Extended intake of METH or a HCD increased general compulsive behavior. Baseline compulsive behavior was not predictive of future METH or HCD intake, but intake of these reinforcers was predictive of post-intake increased compulsivity. In one study, WAY163909 decreased compulsivity (at baseline and after long-term reinforcer intake) and intake of a HCD. These effects were blocked by the 5-HT2C receptor antagonist SB 242084, demonstrating that the 5-HT2C receptor is necessary for the effects of WAY163909. In the final study, WAY163909 dose-dependently decreased METH intake and METH-induced reinstatement, as well as METH-induced dopamine overflow in the nucleus accumbens. These findings are important because they provide evidence that (1) long-term intake of a drug or food reinforcer increases compulsivity, with the amount of reinforcer intake being predictive of the increase in compulsivity, and (2) 5-HT2CRs play a crucial role in both compulsivity and reinforcer intake, as activation of these receptors decreases both measures, regardless of the reinforcer or whether compulsivity is measured at baseline or after prolonged intake of reinforcers. The results suggest that agonists at the 5-HT2CR may represent a promising new avenue for treatment of addiction in general. 

Table of Contents

CHAPTER 1. INTRODUCTION ________________________________________________ 1

1.1       PUBLIC HEALTH RELEVANCE OF ADDICTION ________________________________           2

1.2       THE ADDICTIVE PHENOTYPE ____________________________________________ 3

1.2.1    REINFORCEMENT AND FACTORS IMPLICATED IN ADDICTION___________ 3

1.2.2    NEUROCIRCUITRY AND NEUROCHEMISTRY IMPLICATED IN ADDICTION___ 6

1.3       OVERVIEW OF COMPULSIVITY __________________________________________ 9

1.3.1       COMPULSIVITY IN ADDICTION ___________________________________ 10

1.3.2       DEFINING COMPULSIVITY_______________________________________ 11

1.3.3       BEHAVIORAL MEASURES OF COMPULSIVE ACTION___________________ 12

1.3.4       NEUROANATOMICAL COMPONENTS OF COMPULSIVITY ______________ 14

1.3.5       NEUROCHEMISTRY AND PHARMACOLOGY OF COMPULSIVE BEHAVIOR __ 16

1.3.6       IMPORTANCE OF STUDYING COMPULSIVITY IN FEMALES______________ 19

1.4       OVERALL GOALS AND HYPOTHESES ______________________________________ 20

1.5       FIGURES____________________________________________________________23                                                                                                                             

CHAPTER 2. EFFECTS OF LONG-TERM METHAMPHETMAINE OF HIGH CALORIC DIET

INTAKE ON COMPULSIVITY IN FEMALE RHESUS MONK___________________________ 26

2.1       ABSTRACT___________________________________________________________ 27

2.2       INTRODUCTION ______________________________________________________ 28

2.3       METHODS___________________________________________________________ 31

2.3.1       EXPERIMENTAL DESIGN ________________________________________ 31

2.3.2       SUBJECTS____________________________________________________ 31

2.3.3       COMPULSIVITY MEASUREMENTS_________________________________ 33

2.3.4       INTRAVENOUS DRUG SELF-ADMINISTRATION, EXTINCTION, AND

REINSTATEMENT______________________________________________ 34

2.3.5       FOOD INTAKE ________________________________________________ 37

2.3.6       STATISTICAL ANALYSIS _________________________________________ 37

2.4       RESULTS ____________________________________________________________ 38

2.4.1       BASELINE COMPULSIVITY _______________________________________ 38

2.4.2       DRUG SELF-ADMINISTRATION ___________________________________ 38

2.4.3       FOOD INTAKE ________________________________________________ 40

2.4.4       POST-REINFORCER COMPULSIVITY _______________________________ 41

2.4.5       CORRELATIONS BETWEEN COMPULSIVITY AND REINFORCER INTAKE ____ 41

2.5       DISCUSSION _________________________________________________________ 43

2.5.1       OVERVIEW___________________________________________________ 43

2.5.2       REINFORCER INTAKE DURING THE 6-MONTH PERIOD_________________ 43

2.5.3       EFFECTS OF LONG-TERM REINFORCER INTAKE ON COMPULSIVITY_______ 44

2.5.4       RELATIONSHIP BETWEEN BASELINE COMPULSIVITY AND REINFORCER INTAKE____ 46

2.5.5       COMPULSIVITY, EXTINCTION, AND REINSTATEMENT IN THE METH GROUP_____46

2.5.6       LIMITATIONS OF THE STUDY_____________________________________ 48

2.6       FIGURES ____________________________________________________________ 49

CHAPTER 3. ACTIVATION OF SEROTONIN 2C RECEPTORS REDUCES COMPULSIVITY

AND INTAKE OF A PALATABLE, HIGH CALORIC DIET, BUT NOT A LOW CALORIC

DIET, IN FEMALE RHESUS MACAQUES_________________________________________ 58

3.1       ABSTRACT___________________________________________________________ 59

3.2       INTRODUCTION ______________________________________________________ 60

3.3       METHODS___________________________________________________________ 66

3.3.1       EXPERIMENTAL DESIGN ________________________________________ 66

3.3.2       SUBJECTS____________________________________________________ 67

3.3.3       DRUGS______________________________________________________ 68

3.3.4       COMPULSIVITY MEASUREMENTS_________________________________ 69

3.3.5       5-HT2C RECEPTOR AGONIST AND ANTAGONIST INTERVENTIONS ________ 70

3.3.6       INTRAVENOUS DRUG SELF-ADMINISTRATION_______________________ 72

3.3.7       FOOD INTAKE ________________________________________________ 72

3.3.8       STATISTICAL ANALYSIS _________________________________________ 72

3.4       RESULTS ____________________________________________________________ 73

3.4.1       EFFECTS OF A 5-HT2C RECEPTOR AGONIST ON BASELINE COMPULSIVITY ______73

3.4.2       EFFECTS OF A 5-HT2C RECEPTOR AGONIST ON CONSUMPTION OF A LCD_____________       74

3.4.3       EFFECTS OF A 5-HT2C RECEPTOR AGONIST AND ANTAGONIST ON POST-REINFORCER COMPULSIVITY__75

3.4.4       EFFECTS OF A 5-HT2C RECEPTOR AGONIST AND ANTAGONIST ON CONSUMPTION OF A PALATABLE HCD__ 76

3.5       DISCUSSION _________________________________________________________ 77

3.5.1       OVERVIEW___________________________________________________ 77

3.5.2       EFFECTS OF WAY163909 ON COMPULSIVITY________________________ 78

3.5.3       EFFECTS OF WAY163909 ON A LOW CALORIC DIET VS A PALATABLE HCD _ 80

3.5.4       EFFECTS OF SB 242084ON COMPULSIVITY AND FOOD INTAKE __________           82

3.5.5       LIMITATIONS OF THE STUDY_____________________________________ 82

3.6       FIGURES ____________________________________________________________ 84

CHAPTER 4. EFFECTS OF THE SEROTONIN 2C RECEPTOR AGONIST WAY163909 ON THE

ABUSE-RELATED EFFECTS AND MESOLIMBIC DOPAMINE NEUROCHEMISTRY INDUCED

BY METHAMPHETAMINE IN RHESUS MONKEYS_________________________________ 94

4.1       ABSTRACT___________________________________________________________ 95

4.2       INTRODUCTION ______________________________________________________ 96

4.3       METHODS___________________________________________________________ 98

4.3.1       SUBJECTS____________________________________________________ 98

4.3.2       DRUGS______________________________________________________ 99

4.3.3       SURGERY____________________________________________________ 99

4.3.4       METH SELF-ADMINISTRATION ___________________________________ 100

4.3.5       METH REINSTATEMENT ________________________________________ 101

4.3.6       IN VIVO MICRODIALYSIS________________________________________ 102

4.3.7       STATISTICAL ANALYSIS _________________________________________ 103

4.4       RESULTS ____________________________________________________________ 104

4.4.1       METH SELF-ADMINISTRATION ___________________________________ 104

4.4.2       METH REINSTATEMENT ________________________________________ 105

4.4.3       IN VIVO MICRODIALYSIS________________________________________ 106

4.5       DISCUSSION _________________________________________________________ 107

4.5.1       OVERVIEW___________________________________________________ 107

4.5.2       5-HT2C RECEPTOR AGONISTS ATTENUATE THE ABUSE-RELATED AND

DOPAMINERGIC EFFECTS OF PSYCHOSTIMULANTS___________________ 107

4.5.3       SCHEDULES OF REINFORCEMENT_________________________________ 108

4.5.4       WAY163909 MECHANISMS OF ACTION ____________________________ 109

4.5.5       SEROTONIN 5-HT2 RECEPTORS AND STRIATAL DOPAMINE NEUROTRANSMISSION ____        110

4.5.6  SUMMARY___________________________________________________ 111

4.6       FIGURES ____________________________________________________________ 112

CHAPTER 5. GENERAL DISCUSSION ___________________________________________ 115

5.1       SUMMARY OF RESULTS ________________________________________________ 116

5.1.1       SUMMARY OF CHAPTER 2_______________________________________ 116

5.1.2       SUMMARY OF CHAPTER 3_______________________________________ 117

5.1.3       SUMMARY OF CHAPTER 4_______________________________________ 119

5.2       INTEGRATION OF FINDINGS_____________________________________________ 120

5.2.1       EFFECTS OF EXTENDED REINFORCER INTAKE ON GENERAL COMPULSIVITY ___________ 120

5.2.2       EFFECTS OF EXTENDED ABSTINENCE FROM DRUGS ON GENERAL COMPULSIVITY __________122

5.2.3  EFFECTS OF 5-HT2CRS ON COMPULSIVITY AND REINFORCER INTAKE _____ 123

5.2.4   MECHANISMS UNDERLYING COMPULSIVE AND ADDICTIVE BEHAVIORS ________ 124

5.3       FUTURE DIRECTIONS __________________________________________________ 127

5.4       FINAL CONCLUSIONS __________________________________________________ 130

5.5       FIGURES ____________________________________________________________ 132

CHAPTER 6. REFERENCES ___________________________________________________ 137

List of Tables and Figures

FIGURE                                                           PAGE

CHAPTER 1

FIGURE 1.1 _________________________    23

FIGURE 1.2 _________________________    24

TABLE 1.1 __________________________    25

CHAPTER 2

 FIGURE 2.1 _________________________    49                                          

FIGURE 2.2 _________________________    51

FIGURE 2.3 _________________________    52

FIGURE 2.4 _________________________    53

FIGURE 2.5 _________________________    54

FIGURE 2.6 _________________________    56

FIGURE 2.7 _________________________    57

CHAPTER 3

FIGURE 3.1 _________________________    84                                          

FIGURE 3.2 _________________________    85

FIGURE 3.3 _________________________    86

FIGURE 3.4 _________________________    87

FIGURE 3.5 _________________________    88

FIGURE 3.6 _________________________    89

FIGURE 3.7 _________________________    91

FIGURE 3.8 _________________________    92

Chapter 4

FIGURE 4.1 _________________________    112                                        

 FIGURE 4.2 _________________________    113

FIGURE 4.3 _________________________    114

CHAPTER 5

FIGURE 5.1 _________________________    132                                        

FIGURE 5.2 _________________________    133

FIGURE 5.3 _________________________    136

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