Novel approaches to enhance social cognition by stimulating central oxytocin release using a melanocortin 4 receptor agonist Open Access

Kittelberger, Kara (Fall 2017)

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The evolutionarily conserved neuropeptide oxytocin (OT) modulates sociocognitive functioning by coordinating activity across brain regions responsible for integrating the physiological, motivational, and associative properties of social stimuli. Recently, there has been strong clinical interest in pharmacological targeting of the OT system as a potential treatment of social impairments in psychiatric or neurodevelopmental disorders, including autism spectrum disorder (ASD). To date, effective manipulation of the central OT system in a behaviorally- and ecologically-relevant manner has remained elusive. Social attachment formation in the monogamous prairie vole (Microtus ochrogaster) is an ideal model for the study of OT-dependent sociocognitive behaviors with face, construct, and predictive validity for functional human social cognition. We propose here a novel method of enhancing OT-dependent social cognition and neuronal network processing through the use of a melanocortin 4 receptor (MC4R) agonist, Melanotan II (MTII). Stimulation of MC4Rs enhances stimulus-evoked endogenous central OT release. It is hypothesized that MTII could mirror the behavioral effects of direct exogenous OT, and previous studies in female prairie voles report enhancements in social attachment formation following MTII administration. To demonstrate equivalent efficacy of this novel potential treatment in both sexes, we first successfully replicated these published findings using male subjects. Quantitative analysis of reciprocal social interactions did not reveal any MTII-mediated positive shifts in affiliative social behaviors. We therefore hypothesized MTII administration, and consequent elevations in central OT release, may instead modulate neuronal network processing to affect the perception of social stimuli rather than social interactive behavior itself. In a social exposure context, but not in the homecage, MTII treatment robustly increases neuronal activation in brain regions known to mediate social reward and social motivation, the nucleus accumbens shell (NAcc shell) and prelimbic cortex (PLC). Context-dependent increases in NAcc shell and PLC activation following MTII treatment were significantly attenuated by selective blockade of OT receptors. These results support the hypothesis that MTII administration elevates endogenous central OT release in social contexts and positively modulates social salience processing. Enhancing endogenous OT release with MTII could have significant clinical utility as a pharmacological adjuvant to behavioral therapies, particularly those targeting social reward or social motivation.

Table of Contents

 CHAPTERS                                                                                                            PAGE

1. Oxytocin as a modulator of the social salience network and a target for novel drug development     1

           1.1. Abstract                                                                                                2

           1.2. Introduction                                                                                        3

           1.3. Oxytocin and Social Cognition                                                          4

                      1.3.1. Social information detection and processing                          8

                      1.3.2. Social salience                                                                        11

                      1.3.3. Social motivation and social reward                                       17

                      1.3.4. Social memory                                                                      20

                      1.3.5. Oxytocin and modulation of the social salience network      22

           1.4. Pharmacological Targeting of the Oxytocin System                     23

                       1.4.1. Intranasal oxytocin                                                                 24

                       1.4.2. Melanocortin 4 receptor agonists and endogenous central oxytocin release    27

           1.5. Conclusions                                                                                         28

           1.6. Figures                                                                                                  31

2. Behavioral effects of melanocortin 4 receptor agonists in prairie voles  32

           2.1. Abstract                                                                                              33

           2.2. Introduction                                                                                      34

           2.3.  Methods                                                                                              40

           2.4. Results                                                                                               45

           2.5. Discussion                                                                                            49

           2.6. Figures                                                                                                 53

3. Melanocortin 4 receptor agonists and context-dependent neuronal activation    58

           3.1. Abstract                                                                                                59

           3.2. Introduction                                                                                     60

           3.3.  Methods                                                                                              64

           3.4. Results                                                                                              71

           3.5. Discussion                                                                                            75

           3.6. Figures                                                                                             83

4. General conclusions and future directions                                                   106

           4.1. Conclusions                                                                                    107

                       4.1.1. Project 1: Behavioral effects of a melanocortin 4 receptor agonist in the prairie vole   110

                       4.1.2. Project 2: Context-dependent neuronal network activation in response to MC4R agonism    111

                       4.1.3. General Summary                                                                   113

           4.2. Future Directions                                                                         118

                       4.2.1. Social memory and ventral hippocampal CA1 region      119

                       4.2.2. Contribution of direct extrahypothalamic MC4R stimulation  120

                       4.2.3. Interactions with mesocorticolimbic dopamine pathway    121

                       4.2.4. Possible caveats to clinical applicability of MC4R agonists   123

           4.3. Final Conclusions                                                                               125

5. Appendix                                                                                                128

           5.1. Observations on conducting partner preference testing insuboptimal conditions      128

           5.2. Tables                                                                                                   136

6. References                                                                                                           138

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