Direct Evidence that Stimulation of Neuropeptide Y Y5 Receptor Activates Hypothalamo-Pituitary-Adrenal Axis in Conscious Rats via both Corticotropin-Releasing Factor- and Arginine Vasopressin-Dependent Pathway

Abstract

An abundance of data suggests a crucial role of neuropeptide Y (NPY) as an activator of the hypothamamo-pituitary-adrenal (HPA) axis. However, there is quite limited evidence regarding receptors that mediate this response. Here, we address the possibility that Y(5) receptor subtype may be responsible for NPY-induced activation of HPA axis. For this purpose, the effects of an intracerebroventricular injection of Y(5)-selective agonist, [cPP(1-7), NPY(19-23), Ala(31), Aib(32), Gln(34)]-human pancreatic polypeptide (hPP), on circulating ACTH and corticosterone in conscious rats were evaluated. Central injection of hPP (100 pmol) produced significant increases in plasma ACTH and corticosterone compared with artificial cerebrospinal fluid, and previous treatment with a novel Y(5)-selective antagonist, FMS586 [3-(9-isopropyl-6,7,8,9-tetrahydro-5H-carbazol-3-yl)-1-methyl-1-(2-pyridin-4-yl-ethyl)-urea hydrochloride] (25 mg/kg, po), completely blocked these alterations. Pretreatment with corticotropin-releasing factor (CRF) receptor antagonist (astressin, 10-50 microg/rat, iv) or arginine vasopressin (AVP) receptor antagonist ([deamino-Pen(1), O-Me-Tyr(2), Arg(8)] vasopressin; 3-30 microg/rat, iv) differentially suppressed these increases by 70-80 or 40-50%, respectively. The combined treatment showed no additive effect of these antagonists. Furthermore, an exogenous AVP (0.3 microg/rat, iv)-induced HPA activation was fully inhibited by astressin, suggesting a convergent pathway of AVP receptor signals onto CRF neurons. Central injection of hPP also evoked marked up-regulation of mRNA expression for CRF and AVP in the hypothalamus, which, likewise, were completely reversed by FMS586. Our observations provide the first evidence that selective stimulation of Y(5) receptor provokes activation of the HPA axis and its downstream pathway is chiefly composed of both CRF (primary regulator) and AVP (subordinate to the former) with distinct relative contribution.

Neuropeptide Y mediates the initial hypothalamic–pituitary–adrenal response to maternal separation in the neonatal mouse

“…Similar findings have also been reported for NPY/ agouti-related protein double knockouts, giving further support for this line of reasoning (Qian et al 2002). So far it is still unclear which NPY receptor is responsible for the modulatory role on the HPA axis, as both Y1 and Y5 receptors have been implicated (Dimitrov et al 2007, Kakui & Kitamura 2007.…”

“…CRH neurons in the PVN contain NPY1 (Y1) receptors that seem to mediate the activation of these neurons (Dimitrov et al 2007). In addition, a recent study by Kakui & Kitamura (2007) also provided direct evidence for an involvement of Y5 receptors in regulating HPA axis function in the adult rat. Taken together, these data strongly support our hypothesis that NPY could mediate the initial activation of the HPA axis during prolonged maternal absence.…”

Origins of Addiction Predictably Embedded in Childhood Trauma: A Neurobiological Review

“…A primary mechanism of central NYP is implicated in feeding behavior; and excessive stimulation of CORT in the arcuate nucleus creates a 'vicious circle' of additional NYP release that is implicated in biophysiologic changes consistent with metabolic syndrome. 64) Although food stimulates both peripheral and central pathways, perhaps the imbalanced mechanism involved in food addictions implicates not only NYP but also DYN 21,65) and is regulated by stress. Food (particularly carbohydrate-fat) is commonly known to be a replacement addiction for illicit substances and a standalone addiction associated with CT that leads to obesity, and which is clinically reported as a vehicle to control or avoid emotions.…”

Appetite Regulatory Peptides and Insulin Resistance

“…Central administration of NPY was found to reduce energy expenditure, resulting in reduced brown fat thermogenesis [79], suppression of sympathetic nerve activity [80] and inhibition of the thyroid axis [81]. There are some data that NPY activates hypothalamic-pituitary-adrenal axis (HPA) [82], that is implicated in the regulation of metabolism and energy balance. An acute injection of NPY into the PVN produces increases in circulating ACTH and corticosterone in both conscious and anesthetized rats [83].…”

“…Several of these metabolic effects are still present when increased food intake is prevented by food restriction [85]. It was shown that Y5 receptor subtype is involved in the activation of HPA axis mediated by NPY [82].…”