Prolactin-Releasing Peptide as a Novel Stress Mediator in the Central Nervous System*

Abstract

A1/A2 noradrenergic neurons in the medulla oblongata are well known to mediate stress signals in the central nervous system. Stress activates A1/A2 noradrenergic neurons, and then noradrenaline (NA) stimulates ACTH secretion through hypothalamic CRH. On the other hand, PRL-releasing peptide (PrRP) was recently isolated and was found to be produced by some A1/A2 neurons and the dorsomedial hypothalamic nucleus. We previously demonstrated that PrRP neurons make synapse-like contact with hypothalamic CRH neurons. In fact, we demonstrated that the central administration of PrRP stimulates CRH-mediated ACTH secretion. Furthermore, it has been reported that PrRP neurons in A1/A2 cell groups are colocalized with tyrosine hydroxylase (TH), which is known as the marker enzyme of catecholaminergic neurons. These data strongly suggest that PrRP is related to stress-responsive signal transduction, and PrRP and NA cooperatively modulate the hypothalamo-pituitary-adrenal axis. We therefore examined the effect of water immersion-restraint stress on c-Fos protein accumulation in PrRP- and TH-immunoreactive neurons. The synergistic effects of PrRP and NA on plasma ACTH elevation were also examined. The results clearly showed that c-Fos protein accumulation dramatically increased in the nuclei of A1/A2 and dorsomedial hypothalamic nucleus PrRP neurons. In addition, it was revealed that c-Fos protein was specifically expressed in the PrRP/TH double positive cells in the A1/A2 cell groups. We also demonstrated that the central administration of PrRP and NA in combination at subactive (noneffective) doses clearly induced plasma ACTH elevation. Here we report that PrRP is a novel and important mediator of the hypothalamo-pituitary-adrenal axis for the stress response.

Prolactin-Releasing Peptide Releases Corticotropin-Releasing Hormone and Increases Plasma Adrenocorticotropin via the Paraventricular Nucleus of the Hypothalamus

“…ICV injection of PrRP has been shown to increase plasma ACTH [3, 10]. We have investigated this further by showing this action may occur via the PVN and exploring the possible hypothalamic mechanism of PrRP’s action on plasma ACTH levels.…”

“…We have shown that PVN injection of PrRP rapidly increased ACTH and this effect was maintained for the 40-min duration of the experiment. It is interesting to note that the activation of PrRP neurons by restraint stress, as demonstrated by c-fos expression, is maintained over 6 h [10], which could suggest that PrRP is important in the long-term control of HPA activation in response to stress.…”

“…These NA fibres are believed to be important in hypothalamo-pituitary-adrenal axis (HPA) activation [8]and project to the paraventricular nucleus of the hypothalamus (PVN) [9]. PrRP-IR neurones are found in close apposition with the corticotropin-releasing hormone (CRH) neurones in the parvocellular portion of the PVN [10]. Intracerebroventricular (ICV) administration of PrRP causes neuronal activation in the PVN as demonstrated by the expression of the early gene c-fos and also increases plasma ACTH levels [3].…”

“…Intracerebroventricular (ICV) administration of PrRP causes neuronal activation in the PVN as demonstrated by the expression of the early gene c-fos and also increases plasma ACTH levels [3]. PrRP mRNA expression in the medulla oblongata is increased by restraint stress [10]suggesting that PrRP has a role in the control of the HPA.…”

Central Administration of Neuropeptide B, But not Prolactin-Releasing Peptide, Stimulates Cortisol Secretion in Sheep

“…An icv injection of PrRP also stimulates prolactin [20], ACTH and β-endorphin secretion through a CRHmediated mechanism in the rat [17]. Furthermore, it has been demonstrated that various types of stress, such as restraint and footshock, activate c-Fos accumulation in PrRP neurons in the medulla oblongata in the rat [21][22][23]. …”