Centrally administered adrenomedullin 5 activates oxytocin-secreting neurons in the hypothalamus and elevates plasma oxytocin level in rats

We examined the effects of i.c.v. administration of adrenomedullin 5 (AM5) on the brain of conscious rats. We used porcine AM5 in the present study because rat AM5 has not been detected. We observed Fos-like immunoreactivity (LI) in the hypothalamus and brainstem of conscious rats after i.c.v. administration of AM5 (2 nmol/rat). Fos-LI, measured at 90 min post-AM5 injection, was observed in various brain areas, including the supraoptic (SON) and the paraventricular nuclei (PVN). Dual immunostaining for Fos/oxytocin (OXT) and Fos/arginine vasopressin (AVP) revealed that OXT-LI neurones predominantly colocalized Fos-LI compared with AVP-LI neurones in the SON and the PVN. Plasma OXT levels were significantly increased 5 min after i.c.v. administration of AM5 (1 nmol/rat) compared with vehicle and remained elevated in samples taken at 15 and 30 min without changes in plasma AVP levels at any time. In situ hybridization histochemistry showed that i.c.v. administration of AM5 (0.2, 1 and 2 nmol/rat) caused a marked induction of the expression of the c-fos gene in the SON and the PVN. This induction was significantly but not completely reduced by pretreatment with both the calcitonin gene-related peptide (CGRP) antagonist CGRP-(8-37; 3 nmol/rat) and the AM receptor antagonist AM-(22-52; 27 nmol/rat). Although porcine AM5 has not been detected yet in the brain, these results suggest that centrally administered porcine AM5 may activate OXT-secreting neurosecretory cells in the hypothalamus partly through AM/CGRP receptors and elicit secretion of OXT into the systemic circulation in conscious rats.