Our aim has been to investigate the ability of the rat brain to retain its level of neurotransmitter release over life. We have investigated the neurotransmitter release from the rat brain synaptosomes prelabeled with 3H-DA, 3H-NA, or 3H-5HT, and perfused with Krebs-Ringer medium alone (basal release) or containing a high K+, calcium ionophore, tyramine or amphetamine (evoked release). Brain areas have been dissected of animals 45 days and 4, 6, and 11 months old. The results have shown a gradual reduction of the 3H-NA release evoked by a high K+ from 45 days to 6 months, which is stabilized until 11 months of age. The reduction rate has been relatively different from the brain areas investigated (36% for the frontal cortex and 26% for the hippocampus and cerebellar cortex). A similar reduction has been seen with 3H-5HT released from synaptosomes of the frontal cortex, hippocampus, and striatum. Surprisingly, the 3H-DA release that was evoked by high K+ was greater in rats 11 months old than in younger rats; this effect has been seen in synaptosomes from the caudate and the frontal cortex. The calcium ionophore A23187 has shown a releasing picture similar to a high K + . When we analyzed a nonexocitotic, but probably carrier mediated, release (evoked by tyramine or amphetamine), there was reduced release of all of the above neurotransmitters from 45 days to 11 months of age. We presume that there have been adaptative changes in neurotransmitter evoked release due to changes in C a + + utilization, as inferred from the results from calcium ionophore experiments and carrier performance. Aging seems to have preserved the extracellular neurotransmitter concentrations of Na and SHT, compensating for the decreased carrier performance with a reduced depolarization rate of nerve terminals. DA homeostasis seems to have been altered with normal aging and may produce an elevation in extracellular DA and in its metabolite, yielding free radicals. This mechanism may play a role in degenerative changes associated with normal aging.