THE NONPEPTIDE GROWTH-HORMONE SECRETAGOGUE, MK-0677, ACTIVATES HYPOTHALAMIC ARCUATE NUCLEUS NEURONS IN-VIVO

There is accumulating evidence that the hypothalamic arcuate nucleus p lays an important role in mediating the effects of growth hormone secr etagogues on growth hormone (GH) release from the anterior pituitary g land, One such nonpeptidyl secretagogue, MK-0677, has been shown to di rectly stimulate growth hormone release from isolated pituitary cells but its central actions remain to be established. Therefore, in the pr esent study, we have employed both immunocytochemical and in vivo elec trophysiological techniques to examine the effects of MK-0677 within t he hypothalamic arcuate nucleus of the male rat. In conscious male rat s, both central and systemic injection of MK-0677 induced fos-like imm unoreactivity specifically within the arcuate nucleus indicating selec tive neuronal activation of neurons within this region. MK-0677 induce d-activation was generally confined close to the wall of the third ven tricle, whereas systemic injection of the peptide secretagogue, GHRP-6 , also induced fos-like immunoreactivity in more lateral regions of th e nucleus. In urethane anaesthetized rats, intravenous injection of MK -0677 increased the electrical activity of a population of antidromica lly identified (i.e. neuroendocrine) arcuate neurons with a similar el ectrophysiological profile to cells excited by GHRP-6. The activity of neuroendocrine arcuate neurons excited by MK-0677 injection could be attenuated by a subsequent systemic injection of somatostatin. However , the activity of neuroendocrine arcuate neurons unaffected by MK-0677 injection and the activity of non-neuroendocrine arcuate neurons was unaltered by somatostatin injection, Taken together, the immunocytoche mical and electrophysiological results suggest that systemic and centr al administration of MK-0677 activates a population of neurons in the arcuate nucleus. Furthermore, the inhibitory effects of somatostatin o n MK-0677-induced excitation of these neuroendocrine cells is consiste nt with an action of neurons involved in the regulation of GH release.