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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

Pharmaceutical Research Center, Meiji Seika Kaisha Ltd., Kohoku-ku, Yokohama 222-8567, Japan

Address all correspondence and requests for reprints to: Nobukazu Kakui, Ph.D., Pharmaceutical Research Center, Meiji Seika Kaisha Ltd., 760 Moro-oka-cho, Kohoku-ku, Yokohama 222-8567, Japan. E-mail: nobukazu_kakui{at}meiji.co.jp.

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 Y₅ receptor subtype may be responsible for NPY-induced activation of HPA axis. For this purpose, the effects of an intracerebroventricular injection of Y₅-selective agonist, [cPP^1–7, NPY^19–23, Ala³¹, Aib³², Gln³⁴]-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 Y₅-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 µg/rat, iv) or arginine vasopressin (AVP) receptor antagonist ([deamino-Pen¹, O-Me-Tyr², Arg⁸] vasopressin; 3–30 µg/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 µg/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 Y₅ 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.

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