Neurobehavioral effects, and therapeutic-like potential, of MDMA and cortico-striatal trkB Open Access

Pitts, Elizabeth (Fall 2017)

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Cocaine addiction is a major public health concern with limited treatment options and no FDA approved pharmacological treatments. Addiction is a disorder characterized by maladaptive decision making, habit-like drug seeking, and social impairment. Brain-derived Neurotrophic Factor (BDNF) and its high-affinity receptor tyrosine kinase receptor B (trkB) play an important, but complex, role in mediating cocaine-reinforced behaviors and flexible decision making. Broadly, this thesis examines the role of BDNF-trkB in the extended circuitry of the orbitofrontal prefrontal cortex (oPFC), a brain region necessary for goal-directed decision making and implicated in the etiology of addiction. Additionally, this thesis examines the potential of neurotrophin-based therapeutics in enhancing goal-directed action selection and social behavior. I first show that trkB in the oPFC is necessary for goal-directed decision making, and that trkB in the dorsal striatum bi-directionally regulates flexible decision making. Next, I examine the long-term effects of adolescent cocaine exposure on decision-making and show that 7,8-dihydroxyflavone (7,8-DHF), a novel trkB agonist, blocks cocaine-induced habits, rescuing goal-directed action selection. I also find that 3,4-methylenedioxymethamphetamine (MDMA), a ring-substituted phenethylamine, selectively increases oPFC BDNF and enhances action-outcome decision making in an oPFC trkB-dependent manner. Finally, I examine the pharmacological mechanisms mediating the affiliative social effects of MDMA, finding that increases in social behaviors are 5-HT2A, but not 5-HT1A, receptor dependent. Together, these findings highlight the importance of BDNF-trkB in the oPFC, and connected regions, in flexible decision making and support the therapeutic potential of neurotrophin-based treatments for cocaine addiction. 

Table of Contents

Chapter 1: Prefrontal cortical BDNF-trkB: A regulatory key in cocaine- and food- reinforced behaviors 15

1.1 Context, Author’s Contribution, and Acknowledgement of Reproduction 16

1.2 Abstract 16

1.3 Introduction 16     

1.3.1 The rodent PFC: A brief overview 18

1.3.2 Animal models of drug seeking and habit formation 20

1.3.3 Cocaine rapidly regulates mPFC BDNF and Bdnf, and acute BDNF infusion can decrease cocaine-related responding 21

1.3.4 A history of cocaine exposure increases mPFC BDNF and Bdnf 23

1.3.5 Chronic deviations in typical mPFC BDNF-trkB tone influence locomotor sensitization and cocaine- and food-reinforced behaviors 24

1.3.6 Does mPFC BDNF influence habit-based behavior? 26

1.3.7 Effects of trkB stimulation 27

1.3.8 oPFC BDNF regulates reward-related and goal-directed decision making 28

1.3.9 Does cocaine impact BDNF expression in the oPFC? 31

1.3.10 Regulation of neuron structure 31

1.4 Conclusions 33    

1.5 Dissertation Overview 34

Chapter 2: Bidirectional coordination of actions and habits by trkB 41

2.1 Context, Author’s Contribution, and Acknowledgement of Reproduction 42

2.2 Abstract 42

2.3 Introduction 42     

2.4 Materials and Methods 43

2.4.1 Subjects 43

2.4.2 Intracranial surgery 44

2.4.3 Action-outcome contingency degradation 44

2.4.4 Histology 45

2.4.5 Western blotting 45

2.4.6 Statistical analyses 46

2.5 Results 46

2.5.1 trkB in the oPFC is necessary for goal-directed action selection 46   

2.5.2 trkB in the dorsal striatum bi-directionally regulates decision making 47         

2.6 Discussion 48

Chapter 3: Blockade of cocaine-induced habits by MDMA is trkB-dependent          53

3.1 Context, Author’s Contribution, and Acknowledgement of Reproduction 54

3.2 Abstract 54

3.3 Introduction 55     

3.4 Materials and Methods 56

3.4.1 Subject 56

3.4.2 Drugs 56

3.4.3 Intravenous cocaine self-administration 57

3.4.4 Oral cocaine self-administration 58

3.4.5 Intracranial surgery 59

3.4.6 Food-reinforced instrumental conditioning 59

3.4.7 7,8-DHF-cocaine cross-sensitization 60

3.4.8 Histology 61

3.4.9 Quantitative imaging 61

3.4.10 Western blotting 62

3.4.11 Enzyme-linked immunosorbent assay (ELISA) 62

3.4.12 Statistical analyses 63

3.5 Results 63

3.5.1 Adolescent cocaine exposure has long-term behavioral consequences 63   

3.5.2 trkB stimulation normalizes decision-making strategies following developmental cocaine 64

3.5.3 MDMA stimulates oPFC BDNF and blocks cocaine-induced habits 65

3.5.4 Blockade of cocaine-induced habits by MDMA is trkB-dependent 66

3.5.5 Neurotrophin-dependent oPFC-BLA interactions coordinate outcome-based decision making 67    

3.6 Discussion 67      

3.6.1 Adolescent cocaine exposure has long-term neurobehavioral consequences 68      

3.6.2 Blockade of cocaine-induced habits 69

3.6.3 oPFC BDNF organizes goal-directed action via the BLA 71    

3.6.4 Conclusions 71 

Chapter 4: MDMA increases affiliative behaviors in squirrel monkeys in a serotonin 2A receptor-dependent manner 88

4.1 Context, Author’s Contribution, and Acknowledgement of Reproduction 89

4.2 Abstract 89

4.3 Introduction 90     

4.4 Materials and Methods 92

4.4.1 Subjects 92

4.4.2 Experimental protocol 92

4.4.3 Drugs 94

4.4.4 Data analysis 94

4.5 Results 96

4.5.1 MDMA and its enantiomers increase affiliative social behaviors 96

4.5.2 MDMA and its enantiomers increase affiliative vocalizations 96

4.5.3 MDMA and its enantiomers affect other vocalizations 97

4.5.4 MDMA-induced affiliative behaviors are 5-HT2A, but not 5-HT1A, dependent 97

4.5.5 Repeated administration of MDMA increases huddling in a subject with initially low MDMA-induced social behaviors 98

4.6 Discussion 98

Chapter 5: MDMA: Historical perspectives and future directions 121

5.1 Summary of Results 122

5.2 MDMA: Historical Perspectives 125

5.3 Current Clinical Use of MDMA 126          

5.4 Potential Advantage of R(–)-MDMA 128 

5.5 Future Directions 129      

5.6 Conclusions 132  

Appendix: Complete list of publications to which the author has contributed during her graduate training 134

References 135

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