CENTRAL ADMINISTRATION OF A GROWTH-HORMONE (GH) RECEPTOR MESSENGER-RNA ANTISENSE INCREASES GH PULSATILITY AND DECREASES HYPOTHALAMIC SOMATOSTATIN EXPRESSION IN RATS

To test the hypothesis of the involvement of centrally expressed rat g rowth hormone receptors (rGH-R) in the ultradian rhythmicity of pituit ary GH secretion, adult male rats were submitted to a 60 hr intracereb roventricular 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 infus ed 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 in creasing ODN concentrations resulted in a dose-dependent stimulation o f GH release. In parallel, somatogenic binding sites in the choroid pl exus were decreased by 40%, and levels of rGH-R mRNA were increased in the periventricular nucleus (PeV) but unchanged in the arcuate nucleu s (ARC). Levels of somatostatin mRNA, in the PeV but not in the ARC, w ere lowered by the treatment, Levels of GH-releasing hormone mRNA in t he 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 an terior periventricular hypothalamus.