Food intake and energy balance are among the functions regulated by serotonin in the brain. Recent studies have shown an interaction of serotonergic system with leptin, a protein released from adipose tissue that inhibits feeding behavior and increases fuel expenditure. In this study, leptin labeled with digoxigenin was injected in the lateral cerebral ventricle of 5 young adult rats (4months old) and 5 aged rats (24months old) to assess the effect of aging on the accumulation of exogenous leptin by raphe and hypothalamic neurons. Four aged rats showed an intense leptin accumulation in neuronal cell bodies, mainly at the level of the dorsal raphe nucleus. In contrast, only one young rat showed neuronal accumulation of leptin in dorsal raphe and hypothalamus. Low brain serotonin immunoreactivity was found in all animals with high neuronal leptin accumulation at the raphe nucleus, independently of their age. In contrast, high brain serotonin immunoreactivity was accompanied by a low neuronal accumulation of leptin. To determine whether differences in serotonin content were the cause of the differences in leptin accumulation an inhibitor of serotonin synthesis, p-chlorophenylalanine, was administered to young rats. Serotonin depletion resulted in an enhanced accumulation of leptin in raphe as well as in hypothalamic neurons. These findings indicate that serotonin regulates leptin uptake by neuronal cell bodies of the dorsal raphe and hypothalamus, this suggests that at least part of the effects of serotonin may be mediated by the regulation of neuronal trafficking in the brain.