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

Ewing Corcoran, Sarah (2009)
Dissertation (220 pages)
Committee Chair / Thesis Adviser: Howell, Leonard
Committee Members: Goodman, Mark ; Holtzman, Stephen G ; Muly, E Christopher ; Nader, Michael (Wake Forest University);
Research Fields: Biology, Neuroscience
Keywords: maternal separation; psychostimulants; dopamine; drug self-administration; HPA axis
Program: Laney Graduate School, Biological and Biomedical Sciences
Permanent url: http://pid.emory.edu/ark:/25593/1b0v5

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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