Identifying Novel Therapeutic Strategies for Enhancing Social Cognition Using Functional Animal Models Open Access

Modi, Meera (2012)

Permanent URL: https://etd.library.emory.edu/concern/etds/kk91fk63v?locale=en
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Abstract

Currently, there are no FDA-approved drugs for the treatment of the social impairments characteristic of many psychiatric disorders, including autism and schizophrenia. One potential approach to treating social impairments is to target the neural systems that underlie functional social motivation and information processing in normative populations. Oxytocin (OT) has emerged as a central modulator of social behavior, and the OT system is being actively explored as a pharmacological target for the enhancement of social cognition clinically. However, the therapeutic potential of OT is limited by the biophysical properties of the peptide, include its poor penetration of the blood-brain barrier and its metabolic instability. Consequently, novel methods of enhancing the OT system and the social brain circuit are required to realize the pharmacological treatment of social impairments. Through my doctoral work, I have evaluated and developed novel methods of pharmacologically enhancing social cognition and characterized a functional animal model with predictive validity for prosocial therapeutics.

Alternate methods of enhancing the central OT system were tested. The relative efficacy of peripheral routes of OT administration on increasing central peptide levels to evoke behavioral effects was measured in a rhesus monkey model. In prairie voles, a novel method of increasing central OT through the pharmacological stimulation of oxytocinergic neurons was tested. Peripherally administered melanocortin receptor agonists, Melanotan-II and Pf-446687, are able to recapitulate the behavioral effects of central OT in this model, through an OT-dependent pathway. These findings suggest indirect stimulation of the OT system can result in a functional enhancement of social cognition. Social cognition can also be enhanced in the prairie vole model through the glutamatergic activation of the brain areas involved in the regulation of OT-dependent social behavior. Administration of the NMDA receptor partial agonist, D-cycloserine, prior to a social learning experience also facilitates social cognition through brain areas that regulate the expression of social behavior, the nucleus accumbens and the amygdala. Importantly, preliminary studies indicate that D-cycloserine reduces some of the social impairments in individuals with autism, suggesting that partner preference in the prairie vole may have predictive validity for identifying drugs that enhance the acquisition of social information.

Table of Contents

1. The oxytocin system in drug discovery for autism: animal models and novel therapeutic strategies...1

1.1. Abstract...2
1.2. Introduction...3

1.2.1. Using animal models to understand ASD...4

1.3. ASD phenotypes in genotype based models...5

1.3.1. Social information processing and recognition...5
1.3.2. Social comfort...7
1.3.3. Anxiety...8
1.3.4. Other ASD relevant phenotypes...9
1.3.5. Evidence for construct validity...9
1.3.6. Oxytocin and monogenic forms of ASD...10

1.4. ASD Related Phenotype Based Models...11

1.4.1. Inbred mouse models of social variability...12
1.4.2. Social variation in microtine rodents...13

1.5. Therapeutic strategies for targeting the OT system...15

1.5.1. Intranasal OT...16
1.5.2. Non-peptide agonist...17
1.5.3. Enhancing endogenous OT release...18
1.5.4. Oxytocinase inhibitors...21
1.5.5. Oxytocin manipulations as adjuncts to behavioral therapies...22

1.6. Conclusions...23
1.7. Acknowledgments...24
1.8. Tables and Figures...25

2. Intranasal oxytocin increases plasma but not lumbar cerebrospinal fluid oxytocin concentrations in rhesus monkeys...30

2.1. Abstract...31
2.2. Introduction...32
2.3. Materials and Methods...34
2.4. Results...35

2.4.1. Oxytocin and vasopressin...35
2.4.2. Cortisol...35

2.5. Discussion...36

2.5.1. Undetected central penetration...36
2.5.2. Potential peripheral mechanism...38
2.5.3. Effect of oxytocin administration on vasopressin and cortisol...40
2.5.4. Therapeutic use of oxytocin...41
2.5.5. Conclusion...42

2.6. Acknowledgements...42
2.7. Tables and Figures...43

3. Enhancing oxytocin dependent behavior through the stimulation of melanocortin receptors...46

3.1. Abstract...47
3.2. Introduction...48
3.3. Methods...51

3.3.1. Subjects...51
3.3.2. Partner preference test...51
3.3.3. Localization of the melanocortin 4 receptor in the prairie vole...52
3.3.4. Activation of oxytocin-positive neurons after Melanotan II administration...52
3.3.5. Peripheral administration of Melanotan I and Melanotan II in prairie voles...54
3.3.6. Peripheral administration of Melanotan II in meadow voles...54
3.3.7. Long-term effect of Melanotan II administration in female prairie voles...55
3.3.8. Effect of neonatal Melanotan II on adult social behavior...55
3.3.9. Co-administration of Melanotan II and oxytocin receptor antagonist...55
3.3.10. Central penetration of melanocortin agonists...56
3.3.11. Peripheral administration of Pf-446687 in female prairie voles...58
3.3.12. Statistical analysis...58

3.4. Results...58

3.4.1. Localization of the melanocortin 4 receptor in the prairie vole...58
3.4.2. Activation of oxytocin-positive neurons after Melanotan II administration...59
3.4.3. Peripheral administration of Melanotan I and Melanotan II in prairie voles...59
3.4.4. Peripheral administration of Melanotan II in meadow voles...59
3.4.5. Long-term effect of Melanotan II administration in female prairie voles...60
3.4.6. Effect of neonatal Melanotan II on adult social behavior...60
3.4.7. Co-administration of Melanotan II and oxytocin receptor antagonist...61
3.4.8. Central penetration of melanocortin agonists...61
3.4.9. Peripheral administration of Pf-446687 in female prairie voles...62

3.5. Discussion...62

3.5.1. Effect of melanocortin agonists on partner preference formation...62
3.5.2. Mechanism of Action...63
3.5.3. Differential effects of Melanotan I, Melanotan II and Pf-446687...64
3.5.4. Lack of effect in male prairie and female meadow voles...66
3.5.5. Facilitation of the acquisition of social information...67
3.5.6. Melanocortin 4 receptor agonists as a developmental pharmacotherapy...68
3.5.7. Melanocortin 4 receptor agonists as an alternative to intranasal oxytocin...69
3.5.8. Alternative paradigmatic approach...71
3.5.9. Conclusion...72

3.6. Acknowledgements...73
3.7. Tables and Figures...74

4. D-cycloserine facilitates socially-reinforced learning in an animal model relevant to autism spectrum disorders: implications for servings as an adjunct to behavioral therapies...84

4.1. Abstract...85
4.2. Introduction...86
4.3. Materials and Methods...89

4.3.1. Subjects...89
4.3.2. Peripheral effects of DCS on partner preference in prairie voles...89
4.3.3. Central effects of DCS on partner preference in prairie voles...90
4.3.4. Peripheral effects of DCS on partner preference in meadow voles...92
4.3.5. Data analysis of partner preferences...93

4.4. Results...93

4.4.1. Peripheral DCS administration in prairie voles...93
4.4.2. Central DCS administration in prairie voles...94
4.4.3. Peripheral DCS administration in meadow voles...95

4.5. Discussion...95

4.5.1. DCS facilitates partner preference formation in prairie voles...95
4.5.2. Partner preference as a drug discovery paradigm for social cognition enhancers...96
4.5.3. Selection of animal models...98
4.5.4. Pharmacological adjuncts to behavioral therapies...99
4.5.5. Conclusions...101

4.6. Acknowledgements...101
4.7. Tables and Figures...102

5. General conclusions and future directions...106

5.1. Conclusions...107

5.1.1. Efficacy of direct routes of oxytocin administration...108
5.1.2. Behavioral efficacy of indirect methods of increasing central oxytocin...109
5.1.3. Behavioral efficacy of enhancing the circuits associated with oxytocin dependent prosocial behavior...110
5.1.4. General findings...111
5.1.5. A case for functional animal models...112

5.2. Future Directions...115
5.3. Remaining Questions for the Field...116

5.3.1. Oxytocin: Why is it so complicated?...117
5.3.2. How does oxytocin facilitate social cognition?...119

5.4. Final Conclusions...121
5.5. Tables and Figures...123

6. References...126
7. Appendix I...140

7.1. Oxytocin, vasopressin and social behavior: implications for autism spectrum disorders...140

7.1.1. Abstract...141
7.1.2. Introduction...142
7.1.3. Oxytocin and vasopressin: the social peptides...143

7.1.3.1. Oxytocin...143
7.1.3.2. Vasopressin...144

7.1.4. Evolutionary conservation of neuropeptide structure and social function...145
7.1.5. Neuropeptide and their role in mammalian social behavior...146

7.1.5.1. Social motivation...146
7.1.5.1.1. In rodents...146
7.1.5.1.2. In humans...149
7.1.5.2. Social information processing...150
7.1.5.2.1. In rodents...150
7.1.5.2.2. In humans...152
7.1.5.3. Social attachment...155
7.1.5.3.1. In voles...156
7.1.5.3.2. In sheep...158
7.1.5.3.3. In humans...159

7.1.6. Evidence for disregulation of neuropeptide systems in autism spectrum disorders...161

7.1.6.1. Genetic evidence...161
7.1.6.2. Peripheral evidence...163

7.1.7. Implications for developing pharmacological therapies...164
7.1.8. Conclusions...165
7.1.9. Tables and figures...167
7.1.10. References...177

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