Both leptin and growth hormone secretagogues are believed to have stimulatory effects on the hypothalamic growth hormone pulse generator, though whether these are achieved through the same pathway is unknown. Systemic administration of a normally maximal effective dose of the growth hormone secretagogue GHRP-6 to male rats causes the induction of c-Fos protein in the ventromedial aspect of the hypothalamic arcuate nucleus. The effect of the same dose of GHRP-6 is, however, much greater in animals that have been fasted for 48 h, suggesting that in the food-replete rat, arcuate neurons either show reduced sensitivity to endogenous growth hormone secretagogues or they are under the tonic inhibitory influences of other factors. The major populations of arcuate neurons activated by GHRP-6 have been shown to contain neuropeptide Y or growth hormone-releasing factor, while leptin is thought to be inhibitory to neuropeptide Y neurons. Leptin did not alter the response of the rats to GHRP-6. However, it was able by itself to induce c-Fos protein immunoreactivity in the ventral, including the ventrolateral, arcuate nucleus of fasted rats. This is a clear demonstration of the acute activation of arcuate neurons in the rat following systemic leptin injection and suggests that GHRP-6 and leptin act on the growth hormone axis via different pathways.