Characterization of neuropeptide Y-induced feeding in mice: Do Y1-Y6 receptor subtypes mediate feeding?

The stimulation of food consumption after i.c.v. administration of various neuropeptide Y (NPY) receptor agonists was examined in CD-1 mice. These ago nists, including endogenous peptides NPY, peptide YY (PYY), and pancreatic polypeptide, as well as several N-terminal truncated and synthetic peptides that are prototypic receptor agonists at Y1-Y6 NPY receptors ([Leu(31)Pro( 34)]NPY, NPY2-36, NPY3-36, NPY13-36, PYY3-36, Pro(34)PYY, and D-Trp(32)NPY) , showed varying abilities to elicit food consumption such that PYY > NPY2- 36 = NPY = PYY3-36 > Pro(34)PYY > NPY3-36 >> [Leu(31)Pro(34)]NPY > NPY13-36 = D-Trp(32)NPY = pancreatic polypeptide. Published reports have suggested that NPY-induced feeding is mediated via the Y1 or the Y5 receptor subtypes . However, the relative ability of the various peptide analogs to elicit fe eding differed from the relative ability of these peptides to bind to clone d Y1-Y6 receptors. The effects of prototypic Y1 receptor antagonists on NPY -induced feeding were also evaluated after i.c.v. administration. GR231118 (1229U91), a peptide Y1 antagonist, did not block NPY-induced feeding at th e doses tested. BIBP3226, a nonpeptide Y1 receptor antagonist, as well as i ts opposite enantiomer, BIBP3435, which is inactive at Y1 receptors, blocke d feeding elicited by NPY, [Leu(31)Pro(34)], Or PYY at doses that did not c ause overt behavioral dysfunction. The lack of effects with GR231118 and th e nonstereoselective effects of BIBP3226 suggested that NPY-induced feeding in mice was not mediated via the Yt receptor. Thus, by using currently ava ilable prototypic peptide NPY receptor agonists for Y1-Y6 receptors and pep tide and nonpeptide Y1 receptor antagonists GR231118 and BIBP3226, the medi ation of NPY-induced feeding cannot be unequivocally attributed to any one of the known NPY receptors. It is possible that NPY-induced feeding is medi ated either by a combination of more than one NPY receptor subtype or by a unique NPY receptor subtype. Additional subtype-selective receptor antagoni sts, when available, will help to clarify this issue further.