Central relaxin-3 receptor (RXFP3) activation decreases anxiety- and depressive-like behaviours in the rat

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.

► Icv RXFP3-A2 decreased anxiety-like behaviour in adult male Sprague-Dawley rats.
► Testing in anxiety-like tests 14 days earlier increased depressive-like behaviour.
► Icv RXFP3-A2 decreased depressive-like behaviour in ‘pre-tested’ rats.