Florey Department of Neuroscience and Mental Health - Research Publications

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Author: Gundlach, Andrew × Author: Lawrence, Andrew × End date: 2013 × Start date: 2012 ×

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    Central relaxin-3 receptor (RXFP3) activation decreases anxiety- and depressive-like behaviours in the rat
    Ryan, PJ ; Buechler, E ; Shabanpoor, F ; Hossain, MA ; Wade, JD ; Lawrence, AJ ; Gundlach, AL (ELSEVIER, 2013-05-01)
    Relaxin-3 is a recently discovered neuropeptide and the results of earlier anatomical and pharmacological studies suggest it plays a physiological role in modulating functions such as arousal, learning and memory, food intake and neuroendocrine homeostasis. Relaxin-3 is also postulated to modulate affective behaviour, based on high densities of the relaxin-3 G-protein coupled receptor (RXFP3) in brain areas involved in stress and mood/anxiety, including the central amygdala, bed nucleus of the stria terminalis and hypothalamic paraventricular nucleus (PVN); and strong activation of relaxin-3 neurons by stressors, via activation of corticotropin-releasing factor receptor-1 (CRF1). This study assessed the effect of central administration of a newly developed RXFP3-selective agonist, on anxiety- and depressive-like behaviour in rats. Adult, male Sprague-Dawley rats administered 5 μg [R3A(11-24,C15→A)B] (referred to as RXFP3-A2), intracerebroventricularly, demonstrated decreased anxiety-like behaviour in the light-dark box and elevated plus maze, but not in the open field. Notably, in the repeat forced swim test, central RXFP3-A2 administration decreased immobility in rats that had been subjected to the 'stress' of former exposure to the anxiety tests, but not in experimentally naïve rats. These data implicate relaxin-3/RXFP3 signalling in the modulation of effects of acute (anxiety) and cumulative (depression) neurogenic stressors on behaviour; and suggest a potential for RXFP3 agonists as anxiolytic and anti-depressant agents. In addition, our results demonstrate that exposure of adult Sprague-Dawley rats to tests of anxiety-like behaviour (∼10-14 days prior) can significantly increase immobility time in the repeat forced swim test.
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    Relaxin-3/RXFP3 system regulates alcohol-seeking
    Ryan, PJ ; Kastman, HE ; Krstew, EV ; Rosengren, KJ ; Hossain, MA ; Churilov, L ; Wade, JD ; Gundlach, AL ; Lawrence, AJ (NATL ACAD SCIENCES, 2013-12-17)
    Relapse and hazardous drinking represent the most difficult clinical problems in treating patients with alcohol use disorders. Using a rat model of alcohol use and alcohol-seeking, we demonstrated that central administration of peptide antagonists for relaxin family peptide 3 receptor (RXFP3), the cognate receptor for the highly conserved neuropeptide, relaxin-3, decreased self-administration of alcohol in a dose-related manner and attenuated cue- and stress-induced reinstatement following extinction. By comparison, RXFP3 antagonist treatment did not significantly attenuate self-administration or reinstatement of sucrose-seeking, suggesting a selective effect for alcohol. RXFP3 is densely expressed in the stress-responsive bed nucleus of the stria terminalis, and bilateral injections of RXFP3 antagonist into the bed nucleus of the stria terminalis significantly decreased self-administration and stress-induced reinstatement of alcohol, suggesting that this brain region may, at least in part, mediate the effects of RXFP3 antagonism. RXFP3 antagonist treatment had no effect on general ingestive behavior, activity, or procedural memory for lever pressing in the paradigms assessed. These data suggest that relaxin-3/RXFP3 signaling regulates alcohol intake and relapse-like behavior, adding to current knowledge of the brain chemistry of reward-seeking.