Involvement of the sst1 somatostatin receptor subtype in the intrahypothalamic neuronal network regulating growth hormone secretion: An in vitro and in vivo antisense study

Five somatostatin (SRIH) receptors (sst1-5) have been cloned. Recent anatom ical evidence suggests that sst1 and sst2 may be involved in the central re gulation of GH secretion. Given the lack of specific receptor antagonists, we used selective antisense oligodeoxynucleotides (ODNs) to test the hypoth esis that one or both of these subtypes are involved in the intrahypothalam ic network regulating pulsatile GH secretion. In mouse neuronal hypothalami c cultures the proportion of GHRK neurons coexpressing sst1 or sst2 messeng er RNAs (mRNAs) was identical. In contrast, sst1 mRNAs were more often pres ent than sst2 in SRIH-expressing neurons. Firstly, sst1 antisense ODN in vi tro treatment abolished sst1, but not sst2, receptor modulation of glutamat e 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 wit hout modifying their frequency. In parallel, sst1 antisense ODN strongly di minished sst1 immunoreactivity in the anterior periventricular nucleus and median eminence, as well as sst1 periventricular nucleus mRNA levels. The e ffectiveness of the ssta antisense ODN was attested by the inhibition of hy pothalamic binding of [I-125]Tyr(0)- D-Trp(8)-SRIH. Scrambled ODNs had no e ffect on GH secretion or on sst mRNAs or SRIH binding levels. These results favor a preferential involvement of sst1 receptors in the intrahypothalami c regulation of GH secretion by SRIH.