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The discovery that the GH secretagogues activate NPY neurones led us to consider what is known about these neurones that might help explain what role they play in mediating the central actions of the GH secretagogues. NPY cells are scattered throughout the arcuate nucleus, notably in the ventromedial arcuate nucleus. Although NPY is present in portal blood in concentrations which are higher than in the peripheral circulation it is not clear whether the arcuate NPY cells are true neurosecretory adenohypophysiotropic cells which project to the external zone of the median eminence. Certainly, at least a small number of NPY neurones in the arcuate nucleus must be neuroendocrine cells since about 30% of GHRH neurones appear to co-express NPY. However, it seems unlikely that the GH secretagogues are causing significant release of NPY into portal blood since, in contrast to the GH secretagogues, NPY exerts an inhibitory influence on GH secretion.
The NPY cells in the arcuate nucleus have an estabUshed role in the regulation of feeding behaviour. Multiple daily injections of NPY into the PVN increases daily food intake and body weight. It seems possible therefore that activation of these cells by the GH secretagogues is responsible for the acute effects on feeding behaviour when these compounds are administered directly into the brain ventricles. The arcuate NPY cells give rise to a major intrahj^othalamic pathway; they project to the anterior hypothalamus, the pre-optic area, the paraventricular nucleus (PVN) as well as to the ventromedial and dorsomedial hypothalamus. The arcuate-PVN projection is beUeved to be important for the effects on feeding behaviour and also for activation of the hypothalamo- pituitary adrenal axis. Indeed, activation of NPY cells by GH secretagogues may also explain the small Cortisol response following GH secretagogue administration. In a recent study, we sought to determine whether the arcuate cells projecting to the PVN (a sub-population of which are likely to be NPY-containing) also project to the median eminence (indicating that they are likely to be neuroendocrine cells) and whether these cells respond to systemic GHRP-6 injection. Recordings were made of the electrical activity of individual arcuate neurones, and for each cell, we determined whether it could be antidromically activated from the median eminence and also, from the PVN. Of 43 cells that were identified as projecting to the PVN, only one cell also projected to the median eminence.
Ten of the arcuate cells that project to the PVN were tested with systemic GHRP-6 injection and 3 of these responded with an excitation. We concluded that the arcuate cells that project to the PVN (including NPY cells) are unlikely to be neuroendocrine cells and that about 30% of these cells respond to GHRP-6. Taken together with our previous finding that most of the cells in the arcuate nucleus that are activated by GHRP-6 are neuroendocrine cells, it seems likely that the arcuate nucleus NPY cells activated by GH secretagogue are a subpopulation of neuroendocrine NPY that do not project to the PVN. In retrograde labelling studies we confirmed that a very small proportion of the arcuate cells expressing Fos protein following GHRP-6 injection project to the PVN. In these studies, the retrograde tracer Fluorogold was administered to the PVN via a microdialysis probe such that arcuate cells projecting to the PVN could be detected. Of the total number of arcuate cells detected that were retrogradely labelled as projecting to the PVN (n = 184), approximately 20% expressed Fos protein in response to systemic GHRP-6 injection. These cells, however, only account for a very small proportion (3.8%) of the total number of Fos-positive cells detected (n = 979). Taken together with electrophysiological data, we can conclude that approximately 20-30% of arcuate cells projecting to the PVN are activated by GHRP-6. However, of the total number of cells activated by secretagogues, these comprise a very minor population. It would appear that the NPY population activated by the GH secretagogues do not form an important part of the arcuate-PVN NPY projection previously shown to be important for feeding and for stimulation of the hypothalamo-pituitary-adrenal axis. Thus, we conclude that the GH secretagogues are centrally active compounds that act directly within the arcuate nucleus to activate cells in this region. The target cells for GH secretagogue action are a heterogenous population including both neuroendocrine cells (that are mainly excited by GH secretagogues) and non-neuroendocrine cells (the majority of which show an inhibitory response).
The target cells for GH secretagogue action appear to include both GHRH and NPY cells in this region. Consistent with this hypothesis, GH secretagogue receptors have recently been demonstrated on a sub-population of GHRH neurones and on NPY neurones. Clearly, however, GH secretagogue receptors are present in other parts of the CNS where no effect of these compounds on Fos protein expression has been detected. It will be interesting to discover what physiological role the GH secretagogues have at these sites.