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Involvement of the Sst1 Somatostatin Receptor Subtype in the Intrahypothalamic Neuronal Network Regulating Growth Hormone Secretion: An in Vitro and in Vivo Antisense Study¹

U-159, INSERM Centre Paul Broca (C.L., M.T.B.-P., P.Z., S.C., P.D., E.P., J.E., R.G.), 75014, Paris, France; the Departments of Pediatrics and Neurology and Neurosurgery, McGill University (G.S.T.), Montréal, Québec, Canada H3A 2B4; the Department of Medical Anatomy, Panum Institute, University of Copenhagen (L.H.), DK2200 Copenhagen, Denmark; and Novartis Pharma (D.H.), CH 4002 Basel, Switzerland

Address all correspondence and requests for reprints to: Dr. Jacques Epelbaum, U-159, INSERM, Centre Paul Broca, 2ter rue d’Alésia, 75014 Paris, France. E-mail: epelbaum{at}broca.inserm.fr

Five somatostatin (SRIH) receptors (sst1–5) have been cloned. Recent anatomical evidence suggests that sst1 and sst2 may be involved in the central regulation of GH secretion. Given the lack of specific receptor antagonists, we used selective antisense oligodeoxynucleotides (ODNs) to test the hypothesis that one or both of these subtypes are involved in the intrahypothalamic network regulating pulsatile GH secretion. In mouse neuronal hypothalamic cultures the proportion of GHRH neurons coexpressing sst1 or sst2 messenger RNAs (mRNAs) was identical. In contrast, sst1 mRNAs were more often present than sst2 in SRIH-expressing neurons. Firstly, sst1 antisense ODN in vitro treatment abolished sst1, but not sst2, receptor modulation of glutamate sensitivity and decreased sst1, but not sst2, mRNAs. The reverse was true after treatment with sst2 antisense. Sense ODNs did not alter the effects of SRIH agonists. In a second series of experiments, nonanaesthetized adult male rats were infused for 120 h intracerebroventricularly with ODNs. Only the sst1 antisense ODN diminished the amplitude of ultradian GH pulses without modifying their frequency. In parallel, sst1 antisense ODN strongly diminished sst1 immunoreactivity in the anterior periventricular nucleus and median eminence, as well as sst1 periventricular nucleus mRNA levels. The effectiveness of the sst2 antisense ODN was attested by the inhibition of hypothalamic binding of [¹²⁵I]Tyr⁰-D-Trp⁸-SRIH. Scrambled ODNs had no effect on GH secretion or on sst mRNAs or SRIH binding levels. These results favor a preferential involvement of sst1 receptors in the intrahypothalamic regulation of GH secretion by SRIH.

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