Proceedings of The Physiological Society

Physiology 2016 (Dublin, Ireland) (2016) Proc Physiol Soc 37, PCA283

Poster Communications

Activation of oxytocin systems by systemic Melanotan-II in anesthetized rats

L. Paiva1, M. Ludwig1

1. Centre for Integrative Physiology, University of Edinburgh, Edinburgh, Scotland, United Kingdom.

Oxytocin release within the brain modulates several social behaviours in animals and humans. Furthermore, variations in central oxytocin levels have been linked to mental disorders such as autism and anxiety. The administration of exogenous oxytocin was thought to be a potential approach therapeutically, however, oxytocin does not cross the blood-brain barrier (BBB) in physiologically significant amounts1, 2. An alternative approach to exogenous administration of oxytocin is to stimulate central release of oxytocin using melanocortins3. It has been shown that central injections of alpha-melanocyte stimulating hormone (α-MSH) are a potent stimulus to induce central oxytocin release while inhibiting systemic secretion4, but it also does not penetrate the BBB. Thus, experiments were conducted to test whether intravenous (i.v.) injection of the synthetic α-MSH analogue Melanotan-II (MT-II) is able to induce activation of oxytocin neurons using the immediate early gene product Fos protein as a marker for neuronal activation. Under sodium pentobarbital anaesthesia (40 mg/kg i.v.), adult male rats (300±50g, n=6 per group) were given MT-II (1 mg/kg i.v.) or vehicle (1 ml/kg i.v.). After 90min animals were transcardially fixed, brains removed and relevant brain areas analysed for Fos expression combined with oxytocin immunohistochemistry. Our results show that MT-II induces Fos expression in magnocellular oxytocin neurons of the paraventricular (PVN) and supraoptic (SON) nucleus (Means ± S.E.M: 0.91±0.16 vs 2.60±0.49 cells/104 µm and 2.71±0.71 vs 5.62±0.82 cells/104 µm respectively, p<0.05, Mann-Whitney test). In addition, brain areas receiving peripheral inputs that modulate oxytocin release were also analysed, showing an increased Fos expression in the nucleus tractus solitarius (NTS) (0.25±0.05 vs 0.50±0.07 cells/104 µm, p<0.05); no changes in Fos expression were detected in the anteroventral third ventricle (AV3V) region. Finally, Fos expression induced by MT-II was reduced in oxytocin (PVN: 0.85±0.17 vs 0.18±0.06 cells/104 µm; SON: 2.72±0.26 vs 1.44±0.22 cells/104 µm, p<0.05) and also putative vasopressin cells (SON: 6.21±0.78 vs 3.70±0.70 cells/104 µm, p<0.05) by the prior intracerebroventricular (i.c.v.) administration of the non-selective melanocortin antagonist SHU-9119 (1µg/rat, n=10 per group). These results support that systemic administration of MT-II can be an effective pharmacological tool to induce activation of oxytocin neurons thought central receptors. Whether MT-II is able to induce central oxytocin release, however, is still to be determined.

Where applicable, experiments conform with Society ethical requirements