Centre for Neuroscience - Theses
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ItemRelaxin-3 systems in brain: effects on feeding, anxiety, depression and addiction( 2012)The neuropeptide, relaxin-3 (RLN3), and its major endogenous receptor, RXFP3 (relaxin family peptide receptor 3), have been postulated to modulate feeding, anxiety- and depressive-like behaviour, and reward based on neuroanatomical and neurochemical data. The major aim of the research described in this thesis, therefore, was to determine the effect of centrally administered RXFP3-selective peptides on these functions in the adult rat. Intracerebroventricular (icv) administration of the RXFP3-selective agonist peptides, R3/I5 and RXFP3-A2, and native rat/mouse relaxin-3 (rmRLN3) significantly increased acute food intake in male Sprague-Dawley rats, and this effect was prevented by prior icv injection of the RXFP3-selective antagonist peptides, RXFP3-A3 and R3(B1-22)R. Icv injection of RXFP3-A2 decreased anxiety-like behaviour in male Sprague-Dawley rats in a range of behavioural tests, including the light-dark box and elevated plus maze, and produced antidepressant-like effects in the repeat forced swim test, but notably only in rats that had previously been tested in anxiety-like paradigms. Icv injection of RXFP3-selective agonists had no significant effect on general activity assessed quantitatively in automated locomotor cells. Icv administration of an RXFP3 antagonist (R3(B1-22)R) decreased alcohol but not sucrose self-administration in male inbred alcohol-preferring (iP) rats in a dose-related manner, and decreased cue-induced reinstatement (a model of relapse) for alcohol but not sucrose, suggesting a possible role for relaxin-3/RXFP3 signalling in alcohol-seeking. In addition, endogenous relaxin-3 mRNA expression in the hindbrain nucleus incertus correlated with daily alcohol and sucrose intake in the two-bottle choice paradigm, suggesting a role for endogenous relaxin-3 in modulating intake of ‘rewarding’ substances. Overall, the results from this research suggest that the endogenous relaxin-3/RXFP3 system promotes ‘motivated’ or ‘goal-seeking’ aspects of behaviour. These studies contribute to a deeper understanding of the neurobiology underlying clinical disorders such as obesity, anxiety, depression and addiction, which may in turn lead to novel diagnostics and therapeutic approaches. These important findings are therefore predicted to have a significant impact within the fields of neuropeptide biology and behavioural neuroscience, and are associated with several published or submitted scientific journal articles and reviews. In addition, the data have helped stimulate interest in this research area, with several major pharmaceutical companies expressing interest in the relaxin-3/RXFP3 system as a possible target for the development of therapeutic treatments for individual and co-morbid psychiatric and metabolic disorders.