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NEUROPHARMACOLOGY

Evidence for the Existence of an Additional Class of Neuropeptide Y Receptor Sites in Rat Brain

Douglas Hospital Research Centre, Department of Psychiatry, McGill University, Montreal, Québec, Canada (Y.D., R.Q.); Laboratoire de Physiologie Neurovégétative, Unité Mixte de Recherche Centre National de la Recherche Scientifique-Institut National de la Recherche Agronomique-Université, Aix-Marseille III, Faculté St-Jérôme, Marseille, France (E.M.); and Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Montréal, Québec, Canada (A.F.)

Five distinct neuropeptide Y (NPY) receptors have been cloned thus far. Selective agonists and antagonists have recently been developed allowing for detailed functional studies as to the pathophysiological role of a given subtype as well as receptor binding characteristics and distribution. To precisely investigate the discrete localization and ligand selectivity profile of Y₄ and Y₅ receptors, a series of selective molecules were used as radioligands and competitors in rat brain tissues. Binding data revealed that Y₄ and Y₅ receptor-related agonists and antagonists competed with high affinity for specific ¹²⁵I-[Leu³¹,Pro³⁴]human peptide YY (hPYY) binding in the presence of BIBO3304 [(R)-N-[[4-(aminocarbonylaminomethyl)-phenyl]-methyl]-N²-(diphenylacetyl)-argininamide trifluoroacetate] to mask Y₁ sites as well as specific ¹²⁵I-labeled human pancreatic polypeptide (hPP) binding. Competition binding profiles were best fitted to a two-site model for both radioligands, suggesting the likely recognition of the Y₄ and Y₅ subtypes. We were surprised to find that the visualization of these specific binding sites by receptor autoradiography clearly revealed the distinct distribution of specific ¹²⁵I-[Leu³¹,Pro³⁴]hPYY (in presence of Y₁ and Y₅ blockers) and ¹²⁵I-hPP (in presence of Y₅ blocker) binding sites. Moreover, significant amounts of specific ¹²⁵I-hPP binding were observed in the medial preoptic area, paraventricular nucleus of the hypothalamus, interpeduncular nucleus, and various brainstem nuclei, even after masking Y₄ and Y₅ receptors. Similar results were obtained using ¹²⁵I-hPYY(3-36) in presence of Y₂ and Y₅ blockers. These results suggest the possible existence of at least one additional subtype of NPY receptor sites in the rat brain, with enrichment seen in midbrain and brainstem areas involved in the regulation of food intake and cardiorespiratory parameters.

Address correspondence to: Dr. Rémi Quirion, Douglas Hospital Research Center, 6875 Blvd. LaSalle, Montréal (Verdun), QC, Canada H4H 1R3. E-mail: remi.quirion{at}douglas.mcgill.ca

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