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Evidence That the Inhibition of Luteinizing Hormone Secretion Exerted by Central Administration of Neuropeptide Y (NPY) in the Rat Is Predominantly Mediated by the NPY-Y5 Receptor Subtype¹

Division of Biology of Growth and Reproduction, Department of Pediatrics, University of Geneva School of Medicine (P.D.R., P.B., D.D.P., M.L.A.), 1211 Geneva 14, Switzerland; Ferring Research Ltd. (P.D.R., P.B., D.D.P., A.H., J.-L.J.), Chilworth, United Kingdom SO17 7NP; Instituto Tecnológico e Nuclear (P.D.R.), 2685 Sacavem, Portugal; and Douglass Hospital Research Center, Department of Psychiatry, McGill University (Y.D., R.Q.), Verdun, Québec, Canada H4H 1R3
¹

Address all correspondence and requests for reprints to: Dr. M. L. Aubert, Hopital des Enfants, Hôpitaux Universitaires de Genève, 6 rue Willy-Donzé, 1211 Geneva 14, Switzerland. E-mail: aubert{at}cmu unige.ch.

A number of studies have indicated that neuropeptide Y (NPY) is a central regulator of the gonadotropic axis, and the Y1 receptor was initially suggested to be implicated. As at least five different NPY receptor subtypes have now been characterized, the aim of the present study was to reinvestigate the pharmacological profile of the receptor(s) mediating the inhibitory action of NPY on LH secretion by using a panel of NPY analogs with different selectivity toward the five NPY receptor subtypes. When given intracerebroventricularly (icv) to castrated rats, a bolus injection of native NPY (0.7–2.3 nmol) dose-dependently decreased plasma LH. Peptide YY (PYY; 2.3 nmol) was as potent as NPY, suggesting that the Y3 receptor is not implicated. Confirming previous data, the mixed Y1, Y4, and Y5 agonist [Leu³¹,Pro³⁴]NPY (0.7–2.3 nmol) inhibited LH release with potency and efficacy equal to those of NPY. Neither the selective Y2 agonist C2-NPY (2.3 nmol) nor the selective Y4 agonist rat pancreatic polypeptide affected plasma LH, excluding Y2 and Y4 subtypes for the action of NPY on LH secretion. The mixed Y4-Y5 agonist human pancreatic polypeptide (0.7–7 nmol) as well as the mixed Y2-Y5 agonist PYY_3–36 (0.7–7 nmol) that displayed very low affinity for the Y1 receptor, thus practically representing selective Y5 agonists in this system, decreased plasma LH with potency and efficacy similar to those of NPY, indicating that the Y5 receptor is mainly involved in this inhibitory action of NPY on LH secretion. [D-Trp³²]NPY, a selective, but weak, Y5 agonist, also inhibited plasma LH at a dose of 7 nmol. Furthermore, the inhibitory action of NPY (0.7 nmol) on LH secretion could be fully prevented, in a dose-dependent manner (6–100 µg, icv), by a nonpeptidic Y5 receptor antagonist. This antagonist (60 µg, icv) also inhibited the stimulatory action of NPY (0.7 nmol) on food intake. The selectivity of PYY_3–36, human PP, [D-Trp³²]NPY, and the Y5 antagonist for the Y5 receptor subtype was further confirmed by their ability to inhibit the specific [¹²⁵I][Leu³¹,Pro³⁴]PYY binding to rat brain membrane homogenates in the presence of the Y1 receptor antagonist BIBP3226, a binding assay system that was described as being highly specific for Y5-like receptors. With the exception of [D-Trp³²]NPY, all analogs able to inhibit LH secretion were also able to stimulate food intake. Taken together, these results indicate that the Y5 receptor is involved in the negative control by NPY of the gonadotropic axis.

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