Activation of central neuropeptide YY1 receptors potently stimulates food intake in male rhesus monkeys

The orexigenic role of central neuropeptide Y (NPY) in nonhuman primates ha s been questioned. Therefore, we have studied the effect of central NPY on feeding in ad libitum-fed male rhesus macaques. NPY dose-dependently increa sed food intake, with the maximal effect obtained by 50 mu g (960 min food intake +/- SEM, 104 +/- 5 to 188 +/- 11 g; vehicle vs. NPY; n = 6). Blood g lucose levels were unaffected by intracerebroventricular administration of NPY, but animals receiving either 20 or 50 mu g displayed increased plasma levels of insulin and cortisol at few time points. To assess the pharmacolo gical specificity of this response, a novel Y1 antagonist, [(Ile,Glu,Pro,Da ba,Tyr,Arg,Leu,Arg,Tyr-NH2)(2) cyclic (2,4'),(2',4)-diamide] (Y1(ANT)), was synthesized. Receptor binding experiments demonstrated that Y1(ANT) prefer entially binds to Y1 and Y4 receptors (pK(i) 10.12 +/- 0.06 and 9.11 +/- 0. 05 nmol/L, respectively). Functional analysis revealed that Y1(ANT) is a Y1 antagonist and a partial Y4 agonist. Central administration of Y1(ANT) blo cked NPY-induced feeding. In food-deprived monkeys, Y1(ANT) attenuated the feeding response. However, Y1(ANT) had no effect on food intake in satiated monkeys. Thus, endogenous NPY is likely to be involved in the regulation o f food intake in the nonhuman primate, and this effect is at least partiall y mediated via Y1-like receptors.