Novel approaches to enhance social cognition by stimulating central oxytocin release using a melanocortin 4 receptor agonist Public
Kittelberger, Kara (Fall 2017)
Published
Abstract
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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