Beneficial effects of GH on memory, mental alertness, and motivation have been documented. Many actions of GH are mediated through IGF-I; hence, we investigated whether systemic administration of GH or GH-releasing peptide (GHRP)-6 modulates the brain IGF system. Treatment of adult male rats with GHRP-6 or GH for 1 wk significantly increased IGF-I mRNA levels in the hypothalamus, cerebellum, and hippocampus, with no effect in cerebral cortex. Expression of the IGF receptor and IGF-binding protein (IGFBP)-2 were not affected. Phosphorylation of Akt and Bad was stimulated in areas where IGF-I was increased, with no change in MAPK or glycogen synthase kinase-3beta. This suggests that GH and GHRP-6 activate phosphatidylinositol kinase intracellular pathways involved in cell survival in response to growth factors. Indeed, the antiapoptotic protein Bcl-2 was augmented in these same areas, with no change in the proapoptotic protein Bax. IGFBP-5, also reported to be involved in neuron survival processes, was increased mainly in the hypothalamus, suggesting a possible neuroendocrine role. In conclusion, GH and GHRP-6 modulate IGF-I expression in the central nervous system in an anatomically specific manner. This is coincident with activation of intracellular signaling pathways used by IGF-I and increased expression of proteins involved in cell survival or neuroprotection.