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Volume 16, Number 24, Issue of December 15, 1996 pp. 8140-8148
Copyright ©1996 Society for Neuroscience

Central Administration of a Growth Hormone (GH) Receptor mRNA Antisense Increases GH Pulsatility and Decreases Hypothalamic Somatostatin Expression in Rats

Received Aug. 2, 1996; revised Sept. 25, 1996; accepted Sept. 27, 1996.

Elisabeth Pellegrini¹, Marie Thérèse Bluet-Pajot¹, Françoise Mounier¹, Pamela Bennett², Claude Kordon¹, and Jacques Epelbaum¹

¹ U159 Institut National de la Santé et de la Recherche Médicale, 75014 Paris, France, and ² Department of Medicine, Bristol Royal Infirmary, Bristol BS28HW, United Kingdom

To test the hypothesis of the involvement of centrally expressed rat growth hormone receptors (rGH-R) in the ultradian rhythmicity of pituitary GH secretion, adult male rats were submitted to a 60 hr intracerebroventricular infusion of an antisense (AS) oligodeoxynucleotide (ODN) complementary to the sequence of rGH-R mRNA. Eight hour (10 A.M.-6 P.M.) GH secretory profiles, obtained from freely moving male rats infused with 2.0 nmol/hr of rGH-R AS, revealed a marked increase in GH peak amplitude (150 ± 12 vs 101 ± 10 ng/ml), trough levels (16.2 ± 3.0 vs 5.4 ± 1.4 ng/ml), and number of peaks (2.9 ± 0.3 vs 1.8 ± 0.2). No change was observed in rats treated with an ODN complementary to the prolactin receptor mRNA sequence (2.0 nmol/hr). Infusion of increasing ODN concentrations resulted in a dose-dependent stimulation of GH release. In parallel, somatogenic binding sites in the choroid plexus were decreased by 40%, and levels of rGH-R mRNA were increased in the periventricular nucleus (PeV) but unchanged in the arcuate nucleus (ARC). Levels of somatostatin mRNA, in the PeV but not in the ARC, were lowered by the treatment. Levels of GH-releasing hormone mRNA in the ARC were not affected. These data suggest that GH negative feedback results from a direct effect on central GH receptors and a subsequent activation of hypophysiotropic somatostatin neurons located in the anterior periventricular hypothalamus.

Key words: antisense oligonucleotides; growth hormone receptor; growth hormone pulsatility; somatostatin; growth hormone releasing hormone; in situ hybridization; male rat

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