The nonpeptide growth hormone secretagogue, MK-0677, activates hypothalamic arcuate nucleus neurons in vivo

Abstract

There is accumulating evidence that the hypothalamic arcuate nucleus plays an important role in mediating the effects of growth hormone secretagogues on growth hormone (GH) release from the anterior pituitary gland. One such nonpeptidyl secretagogue, MK-0677, has been shown to directly stimulate growth hormone release from isolated pituitary cells but its central actions remain to be established. Therefore, in the present study, we have employed both immunocytochemical and in vivo electrophysiological techniques to examine the effects of MK-0677 within the hypothalamic arcuate nucleus of the male rat. In conscious male rats, both central and systemic injection of MK-0677 induced fos-like immunoreactivity specifically within the arcuate nucleus indicating selective neuronal activation of neurons within this region. MK-0677 induced-activation was generally confined close to the wall of the third ventricle, whereas systemic injection of the peptide secretagogue, GHRP-6, also induced fos-like immunoreactivity in more lateral regions of the nucleus. In urethane anaesthetized rats, intravenous injection of MK-0677 increased the electrical activity of a population of antidromically identified (i.e. neuroendocrine) arcuate neurons with a similar electrophysiological 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 immunocytochemical and electrophysiological results suggest that systemic and central administration of MK-0677 activates a population of neurons in the arcuate nucleus. Furthermore, the inhibitory effects of somatostatin on MK-0677-induced excitation of these neuroendocrine cells is consistent with an action of neurons involved in the regulation of GH release.