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Title: Hypothalamic actions of growth hormone secretagogues
Author: Kumarnsit, Ekkasit
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2003
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In this study, the rat hypothalamic brain areas; the arcuate nucleus and the ventromedial hypothalamic nucleus, were selected for study of GHRP-6 and L-144,446 effects in vitro. Extracellular recordings showed that electrical activity of neuronal population in the arcuate nucleus was significantly excited by GHRP-6 and L-144,446. Patterns of excitation by either GHRP-6 or L-144,446 were closely similar. The increase in firing rate was observed with latency period of approximately 2 to 5 min. The excitation was sustained for more than 1 h after the secretagogue washout. Interestingly, GHRF-6 was also observed to increase the firing activity of neurones in the ventromedial hypothalamic nucleus. Patterns of increase in firing activity of ventromedial hypothalamic neurones were very similar to those observed in arcuate neurones. This is surprising, because in in vivo studies, Fos protein induction by systemic administration of secretagogues was consistently observed in the arcuate nucleus but not in the ventromedial hypothalamic nucleus. According to our evidence that ventromedial hypothalamic neurones were significantly excited to GHRP-6 in vitro, it was hypothesised that, in vivo, GHRP-6 stimulates neurones in the arcuate nucleus or other nuclei nearby which project their nerve endings to inhibit ventromedial hypothalamic neurones. The majority of neurones in the arcuate nucleus and the ventromedial hypothalamic nucleus that were excited by either L-144,446 or GHRP-6, were significantly inhibited by neuropeptide Y (NPY). Especially in the ventromedial hypothalamic nucleus, 68~% of GHRP-6-excited neurones, compared to 40% of those in the arcuate nucleus, were clearly inhibited by NPY, NPY is a potent orexigenic agent that was previously found to be produced in many neurones in the ventromedial arcuate nucleus. In addition, the existence of a NPY pathway that originates in the arcuate nucleus and projects to the ventromedial hypothalamic nucleus has previously been demonstrated. These results suggest that, in vivo, secretagogues may stimulate NPY neurones in the arcuate nucleus which project their nerve endings to inhibit a sub-population of the ventromedial hypothalamic nucleus. To investigate the mechanism of GHRP-6 action, immunohistochemistry technique was used to detect the induction of Fos, a protein product of the immediate early gene c-fos a protein product of the immediate early gene c-fos, in the accurate nucleus. The results showed that intravenous injection of GHRP-6 significantly increased immunostaining of Fos in the arcuate nucleus.  Pretreatment with intravenous administration of NPY caused 61% reduction of number of Fos-positive neurones in the arcuate nucleus induced by GHRP-6. This findings confirm the effects of GHRP-6 on the electrical activity of the arcuate nucleus and support the idea that this brain area is a central site of action of GHRP-6. This thesis describes site of action of secretagogues in the hypothalamus with in vitro and in vivo data. It also shows the functional involvement of NPY in effects of secretagogues on firing activity and induction of Fos protein in this area.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available