Food intake in free-feeding and energy-deprived lean rats is mediated by the neuropeptide Y-5 receptor

The new neuropeptide Y (NPY) Y-5 receptor antagonist CGP 71683A displayed h igh affinity for the cloned rat NPY Y-5 subtype, but > 1,000-fold lower aff inity for the cloned rat NPY Y-1, Y-2, and Y-4 subtypes, In LMTK cells tran sfected with the human NPY Y-5 receptor, CGP 71683A was without intrinsic a ctivity and antagonized NPY-induced Ca2+ transients. CGP 71683A was given i ntraperitoneally (dose range 1-100 mg/kg) to a series of animal models of h igh hypothalamic NPY levels. In lean satiated rats CGP 71683A significantly antagonized the increase in food intake induced by intracerebroventricular injection of NPY. In 24-h fasted and streptozotocin diabetic rats CGP 7168 3A dose-dependently inhibited food intake. During the dark phase, CGP 71683 A dose-dependently inhibited food intake in free-feeding lean rats without affecting the normal pattern of food intake or inducing taste aversion. In free-feeding lean rats, intraperitoneal administration of CGP 71683A for 28 d inhibited food intake dose-dependently with a maximum reduction observed on days 3 and 4, Despite the return of food intake to control levels, body weight and the peripheral fat mass remained significantly reduced. The dat a demonstrate that the NPY Y-5 receptor subtype plays a role in NPY-induced food intake, but also suggest that, with chronic blockade, counterregulato ry mechanisms are induced to restore appetite.