In 1993 it was shown that an iv injection of GHRP-6 causes activation of cells in the rat hypothalamic arcuate nucleus as reflected by increased electrical activation in a subpopulation of neurosecretory neurons (Fig. 1) and an increased expression of Fos-immunoreactivity in a subpopulation of cells in this region (Fig. 2) (6). Similar central activation follows administration of related, nonpeptide mimetics (7). The arcuate nucleus is the only hypothalamic region to show such a response, though the authors now know that Fos expression is also induced by GHRP-6 in some neurons in the area postrema and of the neighboring nucleus tractus solitarii (12). Fos is the protein product of the immediate early gene (IEG) c-fos, and is thought to be involved as a transcription factor linking electrical activity to changes in gene expression. Fos is expressed in many neuronal systems following activation. In the magnocellular neurosecretory system regulating neurohypophysial hormone secretion, Fos expression has been extensively characterized (13-15), and is established to be, for some systems at least, a reliable and sensitive indicator of neuronal activation in a very wide range of physiological and experimental circumstances. In oxytocin neurons, c-fos mRNA is induced within 10 min following stimuli that increase neuronal activity by a mean of only about 1 spike/s (15).
The GHRP-6-induced activation of Fos expression in arcuate neurons is the consequence of a direct central action since injection of low doses of GHRP-6 (0.1 ^g) into the third ventricle induces a selective Fos expression similar in distribution and equivalent in extent to that induced by an iv injection of 50 ^g of this compound (7). Thus, either GHRP-6 penetrates the blood-brain barrier readily following systemic administration, or its primary central site of action is at specialized brain sites where the blood-brain barrier is relatively permeable. Although the median eminence is known to be one such specialized site, the arcuate nucleus itself is not. In the hypothalamus as at the pituitary, GHRH does not act in the same way as GHRP-6, and central administration of GHRH does not induce Fos expression in the arcuate nucleus.
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