Stimulation of the gonadotropic axis by the neuropeptide Y receptor Y1 antagonist/Y4 agonist 1229U91 in the male rat

Neuropeptide Y (NPY) is a highly potent orexigenic substance that is also k nown to modulate gonadotropin secretion. Five receptor subtypes for NPY hav e been identified, and a potent antagonist for the receptor subtype 1 (Y1), 1229U91, also known as GW1229 or GR231118, has been described. Subsequentl y, 1229U91 was also shown to represent a highly potent agonist for the Y4 r eceptor subtype. Very unexpectedly, intracerebroventricular administration of 1229U91 elicited an intense, dose-dependent surge of both luteinizing ho rmone(LH) and follicle-stimulating hormone (FSH) in intact male rats that l asted for 6 h. Such stimulation was absent when a potent gonadotropin-relea sing hormone antagonist was administered systemically, suggesting that 1229 U91 acts centrally to stimulate gonadotropin-releasing hormone release. 122 9U91 administration had no effect on growth hormone, thyroid-stimulating ho rmone, and corticosterone secretions. In addition to 1229U91, four other pa rent dimer molecules described earlier produced a marked and sustained stim ulation of LH when injected intracerebroventricularly that was proportional to their binding affinity for the Y4 receptor. Central administration of t he specific Y1 antagonist BIBO3304 (20 mu g) had no effect on LH secretion, making it unlikely for 1229U91 to stimulate LH secretion by an antagonisti c action on the Y1 receptor subtype, thus suggesting a Y4 receptor mediatio n. In conclusion, the 1229U91 molecule displays an interesting conformation al epitope that is able to generate large LH surges, possibly by activating Y4 or Y4-like receptor subtypes or by acting on a NPV receptor unrelated t arget. Copyright (C) 2000. Karger AG, Basel.