. Melanotrope secretory cycle is regulated by physiological inputs via the hypothalamus. Am J Physiol Endocrinol Metab 285: E1039-E1046, 2003. First published July 22, 2003 10.1152 10. /ajpendo.00238.2003, it has been shown that background color conditions regulate the overall activity of the frog intermediate lobe by varying the proportions of the two subtypes of melanotropes existing in the gland, the highly active or secretory melanotropes and hormone storage melanotropes, depending on melanocyte-stimulating hormone requirements. However, the factors and mechanisms underlying these background-induced changes are still unknown. In the present study, we investigated whether hypothalamic factors known to regulate melanotrope cell function can induce changes in vitro similar to those caused by background adaptation in vivo. We found that the inhibitors apomorphine (a dopamine receptor agonist) and neuropeptide Y decreased the number of active melanotropes and increased simultaneously that of storage melanotropes. On the other hand, the stimulator TRH increased the number of active cells and concomitantly reduced that of storage cells. Inasmuch as none of these treatments modified the apoptotic and proliferation rates in melanotrope cells, it appears that these hypothalamic factors caused actual interconversions of cells from a subpopulation to its counterpart. Taken together, these findings suggest that the hypothalamus would control melanotrope activity not only through short-term regulation of hormone synthesis and release, but also through a long-term regulation of the secretory phenotype of these cells whereby the activity of the intermediate lobe would be adjusted to fulfill the hormonal requirements imposed by background conditions. dopamine; melanotrope cell heterogeneity; neuropeptide Y; secretory cycle; thyrotropin-releasing hormone IN AMPHIBIANS, melanotrope cells of the intermediate lobe regulate a unique physiological process, the adaptation of skin pigmentation to background color conditions (2, 44). Thus high plasma levels of the hormone produced by these cells, melanocyte-stimulating hormone (␣-MSH), induce the dispersion of the pigment melanin in dermal melanophores, causing darkening of the skin, whereas a low level of ␣-MSH prompts aggregation of the pigment and, consequently, skin paling. In a series of studies carried out in our laboratory (21-23), we have demonstrated that, in the frog Rana ridibunda, the overall activity of the intermediate lobe is adjusted by the proportions of two melanotrope cell subtypes, named high-(HD) and low-density (LD) melanotropes on the basis of their sedimentation characteristics in Percoll density gradients. According to their morphofunctional characteristics, HD melanotropes can be defined as a hormone storage cell subset, because they show high ␣-MSH intracellular content but low mRNA levels of the prohormone precursor proopiomelanocortin (POMC) as well as a low basal ␣-MSH secretory rate, whereas LD cells show opposite features, indicative of high biosynthe...