| Dissertation |
Thesis (M.Sc.) --NUI, 2016 at Department of Anatomy and Neuroscience, UCC. |
| Summary |
Ghrelin is a gut-derived, orexigenic hormone, and is the endogenous ligand of the growth hormone secretagogue receptor 1α (GHS-R1α), which is ubiquitously expressed throughout the periphery as well as in the brain. Ghrelin’s primary function lies in growth hormone secretion from the pituitary gland, maintaining energy homeostasis, and appetite regulation. However, ghrelin also plays a key role in regulating non-homeostatic or hedonic food intake. The research conducted in this thesis focuses on the role of ghrelin and the ghrelin receptor in hedonic eating. A key focus of the research involves the further investigation of the interaction between the GHS-R1α receptor and the serotonin 2C receptor (5-HT2C), as previously demonstrated in the Schellekens lab. Accumulating evidence suggests a role for the interaction between the ghrelinergic and serotonergic system (specifically the 5-HT2C receptor) in the regulation of homeostatic food intake. Here, we investigate the importance of this interaction in relation to hedonic feeding, utilising in vitro and in vivo pharmacological approaches stimulating both receptors in tandem. We demonstrate, to our knowledge for the first time, that lorcaserin, a selective 5-HT2C agonist recently approved for the treatment of obesity, acts as a partial agonist of the GHS-R1α receptor at high concentrations. These findings present a potential novel mechanism of action via which the ghrelin and serotonin systems could interact to modulate food intake. We also show that pharmacological stimulation of the 5-HT2C receptors in vivo attenuates ghrelin-mediated effects on both homeostatic food intake, and hedonic consumption of a sucrose solution. We also endeavoured to model ghrelin-mediated reward behaviour using a conditioned place preference test (CPP), and an operant conditioning paradigm, in order to assess the effect of combined GHS-R1α / 5-HT2C receptor stimulation on ghrelin-mediated reward behaviour. However, we could not successfully model ghrelin-mediated reward using either CPP or operant conditioning. Despite this, the overall conclusions drawn from this thesis support evidence of a functional crosstalk between the GHS-R1 and 5-HT2C receptors, and show, for the first time, that the physiological significance of the GHS-R1α/5-HT2C interaction encompasses hedonic feeding, as well as homeostatic feeding. These findings present exciting potential for the development of new pharmacotherapies in the treatment of eating disorders and obesity, unveiling the possibility of a combined pharmacotherapy to treat disorders of the ghrelinergic system, such as obesity, eating disorders, and some addictions. |
| Subject |
Neurotransmitter receptors.
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Neurosciences.
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Brain.
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| Collection |
Theses Masters (Research)
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Theses Anatomy and Neuroscience Department
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| Description |
115 pages ; 30 cm. |
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