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Neuropeptide Y Inhibits the Biosynthesis of Sulfated Neurosteroids in the Hypothalamus through Activation of Y₁ Receptors

European Institute for Peptide Research (IFRMP 23), Laboratory of Cellular and Molecular Neuroendocrinology, INSERM U-413, UA Centre National de la Recherche Scientifique, University of Rouen (D.B., J.-L.D.-R., L.G., A.G.M.-N., H.V.), 76821 Mont-Saint-Aignan, France; Department of Neuroscience, Unit of Pharmacology, Uppsala University (R.F., D.L.), 75124 Uppsala, Sweden; Institut National de la Recherche Scientifique-Institut Armand Frappier, University of Quebec (A.F.), Pointe-Claire, Montréal, Canada H9R 1G6; and Medical Research Council Group in Molecular Endocrinology, Laval University Medical Center (V.L.-T., G.P.), Québec, Canada G1V 4G2

Address all correspondence and requests for reprints to: Dr. Hubert Vaudry, European Institute for Peptide Research (IFRMP 23), Laboratory of Cellular and Molecular Neuroendocrinology, INSERM U-413, UA Centre National de la Recherche Scientifique, University of Rouen, 76821 Mont Saint Aignan, France. E-mail: . hubert.vaudry{at}univ-rouen.fr

We have recently shown that hydroxysteroid sulfotransferase (HST), the enzyme responsible for the biosynthesis of pregnenolone sulfate (⁵PS) and dehydroepiandrosterone sulfate (DHEAS), is expressed in neurons located in the anterior preoptic area and the dorsal magnocellular nucleus of the frog diencephalon. As these two nuclei are richly innervated by NPY-immunoreactive fibers, we investigated the possible implication of NPY in the control of ⁵PS and DHEAS biosynthesis. Double labeling of frog brain sections revealed that 42% of the HST-immunoreactive perikarya in the diencephalon were contacted by NPY-containing fibers. In situ hybridization studies showed that Y₁ and Y₅ receptor mRNAs are expressed in the anterior preoptic area and the dorsal magnocellular nucleus. Pulse-chase experiments with ³⁵S-labeled 3'-phosphoadenosine 5'-phosphosulfate as a sulfate donor demonstrated that frog NPY (fNPY) inhibited the conversion of [³H]⁵P and [³H]dehydroepiandrosterone ([³H]DHEA) into [³H,³⁵S]⁵PS and [³H,³⁵S]DHEAS by diencephalic explants. The inhibitory effect of fNPY on ⁵PS and DHEAS formation was mimicked by (pPYY) and [Leu³¹,Pro³⁴]pNPY, which is an agonist for non-Y₂ receptors in mammals, and was completely suppressed by the Y₁ receptor antagonist BIBP3226. Conversely, the Y₂ receptor agonist pNPY-(13–36) and the Y₅ receptor agonist [D-Trp³²]pNPY did not significantly modify the biosynthesis of [³H,³⁵S]⁵PS and [³H,³⁵S]DHEAS. The present study provides the first evidence for the innervation of neurosteroid-producing neurons by NPY fibers. Our data also demonstrate that NPY, acting via Y₁ receptors, exerts an inhibitory effect on the biosynthesis of sulfated neurosteroids.

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