Neuropeptide Y receptor(s) mediating feeding in the rat: characterization with antagonists Carlo Polidori a, *, Roberto Ciccocioppo a , Domenico Regoli b , Maurizio Massi a a Department of Pharmacological Sciences and Experimental Medicine, University of Camerino, 62032 Camerino, (MC) Italy b Department of Experimental and Clinical Medicine, University of Ferrara, 44100 Ferrara (FE), Italy Received 11 May 1999; accepted 27 September 1999 Abstract The present study evaluated the effect of the neuropeptide Y (NPY) Y1 receptor antagonists BIBO 3304 and SR 120562A and of the Y5 receptor antagonists JCF 104, JCF 109, and CGP 71683A on feeding induced either by NPY or food deprivation. In a preliminary experiment, NPY was injected into the third cerebroventricle (3V) at doses of 0.07, 0.15, 0.3, or 0.6 nmol/rat. The dose of 0.3 nmol/rat, which produced a cumulative 2-h food intake of 11.2  1.9 g/kg body weight, was chosen for the following experiments. The antagonists were injected in the 3V 1 min before NPY. The Y1 receptor antagonist BIBO 3304 significantly inhibited NPY-induced feeding at doses of 1 or 10 nmol/rat. The Y1 receptor antagonist SR 120562A, at the dose of 10 but not of 1 nmol/rat, significantly reduced the hyperphagic effect of NPY, 0.3 nmol/rat. The Y5 receptor antagonists JCF 104 and JCF 109 (1 or 10 nmol/rat) and CGP 71683A (10 or 100 nmol/rat) did not significantly modify the effect of NPY, 0.3 nmol/rat. However, JCF 104 (10 nmol/rat) and CGP 71683A (100 nmol/rat), but not JCF 109 (10 nmol/rat), significantly reduced food intake during the interval from 2 to 4 h after injection of a higher dose, 0.6 nmol/rat, of NPY. Feeding induced by 16 h of food deprivation was significantly reduced by the Y1 receptor antagonist BIBO 3304 (10 nmol/rat), but it was not significantly modified by the same dose of SR 120562A or JCF 104. These findings support the idea that the hyperphagic effect of NPY is mainly mediated by Y1 receptors. The results obtained with JCF 104 and CGP 71683A suggest that Y5 receptors may have a modulatory role in the maintenance of feeding induced by rather high doses of NPY after the main initial feeding response. © 2000 Elsevier Science Inc. All rights reserved. Keywords: Neuropeptide Y; Neuropeptide Y antagonists; Food intake; BIBO 3304; JCF 104; JCF 109; SR 120562A; CGP 71683A; Nociceptin 1. Introduction Neuropeptide Y (NPY), a 36-amino acid neuropeptide isolated from porcine brain [32,33], is considered to be the most abundant and widely distributed neuropeptide present in the mammalian central and peripheral nervous system [2]. The hypothalamus and in particular the paraventricular nucleus (PVN) show high levels of NPY [1]; the hypotha- lamic levels of NPY have been reported to increase in fasting animals and to return to normal levels upon feeding [16,27]. Since the first reports of the hyperphagic effect of NPY [7,22], different investigators have striven to establish which NPY receptor subtype is involved in feeding behav- ior. A decade ago, two NPY receptor subtypes, Y1 and Y2, were pharmacologically characterized [34]; later on, a Y3 receptor was proposed, but not cloned [35]. A fourth recep- tor (Y4) was cloned and characterized by its high affinity for the rat pancreatic polypeptide (PP) [3]. More recently, two additional NPY receptors have been cloned [11]; the first, described as Y5 receptor, has been pharmacologically char- acterized. The second, Y6, or PP2, has been cloned from the mouse, but it is inactive in man and absent in the rat [23]. Initially, it was proposed that the NPY Y1 receptor mediates the hyperphagic effect of NPY in rodents, because agonists selective for this receptor stimulate feeding after central administration [17]. The Y1 receptor antagonists 1229U91 and BIBO 3304 have been reported to inhibit NPY-induced food intake in freely feeding and drinking rats [19,36]. More recently, several authors have proposed that the hyperphagic effect of NPY may be mediated by Y5 recep- * Corresponding author. Tel.: +39-0737-403307; fax: +39-0737- 630618. E-mail address: polidori@cambio.unicam.it (C. Polidori) Peptides 21 (2000) 29 –35 0196-9781/00/$ – see front matter © 2000 Elsevier Science Inc. All rights reserved. PII: S0196-9781(00)00170-9