Early life stress, HPA axis function and sensitivity to psychomotorstimulants in nonhuman primates Public

Abstract

Abstract

Early life stress, HPA axis function and sensitivity to psychomotor stimulants in nonhuman primates

By Sarah Ewing Corcoran

Substance abuse and dependence are major public health concerns and exposure to stressors, particularly early in life, appears to be a strong determinant of increased vulnerability to drug use in humans. These studies utilized a nonhuman primate model of early life stress, in the form of maternal separation, to determine if changes in sensitivity to and increases in the propensity to self-administer psychostimulant drugs were a result of exposure to these stressors. The present studies also examined the long-term effects of maternal separation on behavioral and HPA axis reactivity in rhesus monkeys. As compared with controls, maternally separated monkeys exhibited reduced behavioral output and reduced rates of responding during acquisition and maintenance of cocaine self-administration and across a range of doses of both cocaine and amphetamine. Maternally separated monkeys also failed to exhibit the stimulant-induced increases in motor activity that were observed in control monkeys. However, these differences could not be explained by differences in dopamine D2 receptor binding potential or in drug- induced increases in extracellular dopamine. Control and maternally separated monkeys also did not differ in behavioral reactivity as measured with acoustic startle under baseline conditions or following stimulant challenges. No differences between groups were seen in HPA axis response to an acute injection of cocaine. These results do not provide support for early life stress leading to enhanced sensitivity to the reinforcing and psychomotor effects of stimulants in the nonhuman primate model employed.

Table of Contents

Table of Contents Specific Aims ....................................................................................................................................... 1 Chapter 1: Introduction and Background ................................................................................................ 2

SUBSTANCE ABUSE AND DEPENDENCE ........................................................................................................ 2 Treatment and Prevention ....................................................................................................................... 3 Risk Factors .......................................................................................................................................... 3 PSYCHOSTIMULANTS .............................................................................................................................. 5 DOPAMINE NEUROCHEMISTRY ................................................................................................................... 8 HPA AXIS INTERACTION WITH DOPAMINE SYSTEM ...................................................................................... 12 STRESS AND HPA AXIS FUNCTION ............................................................................................................ 14 Receptor distribution ............................................................................................................................. 15 Actions of glucocorticoids and mineralocorticoids ....................................................................................... 16 Negative feedback ................................................................................................................................ 17 Circadian rhythmicity of HPA axis ............................................................................................................ 18 Exposure to chronic stress .................................................................................................................... 18 MATERNAL SEPARATION AS AN EARLY LIFE STRESSOR ................................................................................ 20 Single 24 hour maternal separation ......................................................................................................... 20 Repeated or periodic maternal separations ............................................................................................... 21 Handled vs. Non-handled ....................................................................................................................... 21 Maternal privation ............................................................................................................................... 22 Peer or nursery rearing ........................................................................................................................ 22 Repeated maternal separation ............................................................................................................... 23 Variable foraging demand ..................................................................................................................... 23 STRESS AND DRUG ABUSE ..................................................................................................................... 24 SUMMARY AND RATIONALE .................................................................................................................... 27 Chapter 2: Subject Information and Maternal Separation paradigm ........................................................ 30 GENERAL ............................................................................................................................................ 30 MATERNAL SEPARATION PARADIGM ......................................................................................................... 31 Chapter 3: Effects of early life stress on the reinforcing effects of psychostimulants .........................................................................................................................................................39 ABSTRACT ......................................................................................................................................... 39 INTRODUCTION ................................................................................................................................... 40 Drug self-administration ....................................................................................................................... 41 Stimulant-induced locomotor activity ..................................................................................................... 43 Dopamine .......................................................................................................................................... 45 In vivo microdialysis............................................................................................................................. 47 Summary and Rationale ....................................................................................................................... 49 MATERIALS AND METHODS ................................................................................................................... 49 Surgery ............................................................................................................................................ 49 Apparatus ......................................................................................................................................... 51 Drug self-administration ...................................................................................................................... 51

Locomotor Activity ............................................................................................................................. 56 Dopamine D2 Receptor Binding Potential ................................................................................................. 56 Radiochemistry ................................................................................................................................. 56 Imaging protocol ............................................................................................................................... 57 In vivo Microdialysis ........................................................................................................................... 58 Drugs .............................................................................................................................................. 59 Data Analysis .................................................................................................................................... 60

RESULTS .......................................................................................................................................... 62 Drug self-administration ...................................................................................................................... 62 Locomotor Activity ............................................................................................................................. 65 Dopamine D2 Receptor Binding Potential .................................................................................................. 78 In vivo microdialysis............................................................................................................................. 78 DISCUSSION ....................................................................................................................................... 88 Drug self-administration ....................................................................................................................... 88 Locomotor activity .............................................................................................................................. 89 Dopamine ........................................................................................................................................... 90 Chapter 3: Long term impact of early life stress on behavioral and HPA axis reactivity ...........................................................................................................................................96 ABSTRACT .......................................................................................................................................... 96 INTRODUCTION .................................................................................................................................... 97 Maternal separation phenotype ............................................................................................................... 97 PET imaging with [¹⁸F]Fluorodeoxyglucose ................................................................................................ 99 Factors affecting glucose metabolism ..................................................................................................... 100 Acoustic startle ................................................................................................................................... 101 Factors affecting startle reactivity ......................................................................................................... 104 HPA axis function and reactivity ............................................................................................................. 106 Summary and Rationale ........................................................................................................................ 110 METHODS AND MATERIALS .................................................................................................................... 111 PET imaging with [¹⁸F]fluorodeoxyglucose ............................................................................................... 111 Acoustic startle .................................................................................................................................. 111 Cortisol measures in infants .................................................................................................................. 114 Cortisol and ACTH response to cocaine challenge ...................................................................................... 114 Drugs ................................................................................................................................................ 116 Data Analysis ......................................................................................................................... ............ 116 RESULTS ............................................................................................................................................ 118 PET imaging with [¹⁸F]fluorodeoxyglucose ................................................................................................ 118 Acoustic startle ................................................................................................................................... 118 Cocaine and Amphetamine pretreatments ................................................................................................ 118 Dopamine agonist pretreatments ............................................................................................................ 122 Cortisol following separation challenge ..................................................................................................... 131 Diurnal rhythm of cortisol ...................................................................................................................... 131 Plasma cortisol and ACTH following cocaine challenge ................................................................................. 136 DISCUSSION ....................................................................................................................................... 141

Cerebral glucose metabolism ................................................................................................................. 141 Acoustic startle .................................................................................................................................. 142 Cortisol response to separation challenge and diurnal rhythm ...................................................................... 144

Cortisol and ACTH following cocaine challenge ........................................................................................... 145 Chapter 4: General Discussion ..............................................................................................................150

LIMITATIONS ....................................................................................................................................... 163 CLOSING REMARKS ................................................................................................................................ 164 References ..........................................................................................................................................166

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience
Mot-clé	dopamine drug self-administration HPA axis psychostimulants maternal separation
Committee Chair / Thesis Advisor	Howell, Leonard, Emory University
Committee Members	Nader, Michael, Wake Forest University Goodman, Mark, Emory University Holtzman, Stephen G, Emory University Muly, E Christopher, Emory University

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