The effects of ketamine on functional brain networks in awake nonhuman primates and the therapeutic potential for treatment of substance abuse Embargo

Maltbie, Eric (Fall 2017)

Permanent URL: https://etd.library.emory.edu/concern/etds/vh53wv76t?locale=en
Published

Abstract

At present, there is considerable interest in improving the understanding of the unique effects of the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, ketamine. Sub-anesthetic infusions of ketamine induce acute psychotomimetic effects, but also produce prolonged neurobiological changes with therapeutic efficacy for treating depression in human subjects. However, the underlying mechanisms mediating these effects remain poorly understood. Building on the recent development of methodology allowing for the collection of quality pharmacological MRI (phMRI) data in awake nonhuman primates (NHPs), this dissertation examines the neural circuitry underlying both the psychotomimetic and therapeutic effects of ketamine. Ketamine induced robust and extensive brain activation and strengthened functional connectivity (FC) in several brain networks, including fronto-striatal circuitry known to be disrupted by cocaine. Subsequently, the efficacy of ketamine for the treatment of cocaine abuse was investigated. Ketamine pretreatment attenuated both the effects of cocaine on fronto-striatal (and whole-brain) FC and cocaine-seeking behavior. In conclusion, phMRI in awake NHPs enables valuable, behaviorally relevant translational imaging models. Ketamine increases FC in fronto-striatal circuits responsible for executive control over reward-based decision making and attenuates the effects of cocaine on both FC and behavior. These findings support the therapeutic potential of ketamine in the treatment of substance use disorders.

Table of Contents

Chapter 1: Ketamine and pharmacological imaging: use of functional

magnetic resonance imaging to evaluate mechanisms of action                         1

1.1 Context, Author’s Contribution, and Acknowledgement of

Reproduction                                                                                               2

1.2 Abstract                                                                                                  2

1.3 Introduction                                                                                         3

            1.3.1 - Neural Mechanisms                                                                             4

1.4 Pharmacological Imaging Methods                                                6

              1.4.1 - Brain Activation                                                                                    7

              1.4.2 - Functional Connectivity                                                                     8

1.5 Pharmacological Imaging and the Behavioral Effects

of Ketamine                                                                                            10

            1.5.1 - Psychotomimetic effects                                                                      10

              1.5.2 - Antidepressant effects                                                                        19

1.6 Discussion                                                                                             21

1.7 Future Directions                                                                                23

              1.7.1 - phMRI and ketamine mechanism of action                                 23

              1.7.2 - phMRI and translational models                                                    25

1.8 Conclusions                                                                                           27

1.9 Dissertation Overview                                                                       28

 

Chapter 2: Ketamine-induced effects on brain activation in conscious

nonhuman primates                                                                                             35

2.1 Context, Author’s Contribution, and Acknowledgement of

Reproduction                                                                                              36

2.2 Abstract                                                                                                 36

2.3 Introduction                                                                                         37

2.4 Materials and Methods                                                                      40

                        2.4.1 - Subjects                                                                                                     40

                            2.4.2 - MRI data acquisition                                                                         41

                            2.4.3 - Drug infusion protocols                                                                     42

                            2.4.4 - Pharmacological MRI data analysis                                            43

                            2.4.5 - Clinical ratings of behavior                                                             50

2.5 Results                                                                                                   51

                        2.5.1 - Blood plasma drug levels                                                                   51

                            2.5.2 - Ketamine-induced BOLD activation                                            51

                            2.5.3 - Reduction in ketamine-induced activation by risperidone

pretreatment                                                                                                      52

2.5.4 - Ketamine-induced effects within a priori ROIs                            52

2.5.5 - ROI-averaged Group-mean Time Courses                                 53

                            2.5.6 - Clinical ratings of behavior                                                             53

2.6 Discussion                                                                                             53

 

Chapter 3: Ketamine-induced effects on functional connectivity in

conscious nonhuman primates                                                                          69

3.1 Context, Author’s Contribution, and Acknowledgement of

Reproduction                                                                                              70

3.2 Abstract                                                                                                 70

3.3 Introduction                                                                                         71

3.4 Materials and Methods                                                                      74

            3.4.1 - Subjects                                                                                                    74

                             3.4.2 - Drug infusion protocols                                                                     75

                             3.4.3 - fMRI Data Analysis                                                                            76

3.5 Results                                                                                                   79

            3.5.1 - Blood plasma drug levels                                                                   79

              3.5.2 - Ketamine-induced changes in FC to dlPFC                                 79

              3.5.3 - Ketamine-induced changes in FC to SgC                                      80

              3.5.4 - Ketamine-induced changes in FC to Amygdala                             80

            3.5.5 - Ketamine-induced changes in FC to Nucleus Accumbens      81

              3.5.6 - Ketamine-induced changes in FC to other ROIs                            81

              3.5.7 - Ketamine-induced inter-hemispheric asymmetry

in FC networks                                                                                     82

3.6 Discussion                                                                                             83

            3.6.1 - Insights into the results of the ketamine drug infusion

phMRI study                                                                                                                     86

              3.6.2 - Limitations                                                                                            86

3.7 Conclusions                                                                                          88

 

Chapter 4: Effects of ketamine treatment on cocaine-induced changes

to functional connectivity in conscious nonhuman primates                        107

4.1 Context, Author’s Contribution, and Acknowledgement of

Reproduction                                                                                              108

4.2 Abstract                                                                                                 108

4.3 Introduction                                                                                         110

4.4 Methods                                                                                                 112

4.4.1 - Subjects                                                                                                   112

                            4.4.2 - Surgery and habituation to MRI                                                    112

4.4.3 - MRI data acquisition                                                                        113

4.4.4 - Drug infusion protocol                                                                      113

4.4.5 - fMRI Data Quality Control                                                              114

4.4.6 - Ketamine treatment                                                                           114

4.4.7 - fMRI preprocessing and spatial normalization                            114

4.4.8 - FC analysis                                                                                            115

4.4.9 - Data Analysis                                                                                       116

4.4.10 - Cocaine Self-administration                                                         116

4.4.11 - Experimental timeline                                                                      116

4.5 Results                                                                                                   117

            4.5.1 - Acute cocaine administration robustly decreased FC         117

              4.5.2 - Ketamine pretreatment attenuated cocaine-induced

changes in FC                                                                                       118

4.5.3 - The effects of cocaine on FC predicted response rates

during self- administration                                                            119

4.5.4 - Chronic cocaine self-administration robustly

decreased FC                                                                                         119

4.5.5 - Acute effects of cocaine on FC following chronic

                                           self-administration                                                                           120

4.5.6 - Effects of ketamine pretreatment on FC after

self-administration                                                                           121

4.5.7 - Individual subject results for dlPFC-NAcc FC                            122

4.6 Discussion                                                                                             123

4.6.1 - Limitations                                                                                            126

4.7 Conclusions                                                                                          127

Chapter 5: Investigating the effects of ketamine treatment on reinstatement

and reacquisition of cocaine self-administration in rhesus monkeys       138

5.1 Context, Author’s Contribution, and Acknowledgement of

Reproduction                                                                                              139

5.2 Abstract                                                                                                 139

5.3 Introduction                                                                                         140

5.4 Methods                                                                                                 142

5.4.1 - Subjects                                                                                                    142

                             5.4.2 - Surgery                                                                                                   142

5.4.3 - Cocaine self-administration                                                            143

5.4.4 - Ketamine treatment                                                                            144

5.4.5 - Reinstatement                                                                                       144

5.4.6 - Reacquisition                                                                                        145

5.4.7 - Data analysis                                                                                        146

5.5 Results                                                                                                   146

            5.5.1 - Self-administration                                                                             146

              5.5.2 - Reinstatement                                                                                      147

              5.5.3 - Reacquisition                                                                                        148

5.6 Discussion                                                                                             149

 

Chapter 6: Clinical use of ketamine, future directions, and

limitations                                                                                                               158

            6.1 - Results Summary                                                                              159

            6.2 - Clinical use of sub-anesthetic ketamine treatment                        163

            6.3 - Future directions for translational models using phMRI

in awake NHPs                                                                                164

            6.4 - Limitations                                                                                         165

            6.5 - Conclusions                                                                                        167

 

Appendix: Complete list of publications to which the author has

contributed during his graduate training                                                        168

 

 

References                                                                                                               169

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