The influence of feeding rats only half the amount of their normal daily intake of a complete rat chow on the affinity and the density of serotonin (5-HT) transporters was measured in membrane preparations of the frontal cortex and the midbrain by a [3H]paroxetine binding assay. In young rats (10 weeks), a significant reduction of about 30% of the Bmax values of [3H]paroxetine binding occurred in the frontal cortex after 1 and 2 weeks of restricted food intake. No starvation-induced decline of the density of 5-HT transporters was seen in the midbrain. When older rats (50 weeks) were subjected to the same 50% reduction of daily food intake for 2 weeks, no such down-regulation of the density of cortical 5-HT transporters was observed. The affinity of the 5-HT transporters, as indicated by the unchanged Kd values of [3H]paroxetine binding, was not affected by semistarvation in both regions and at both ages. The observed decline of [3H]paroxetine binding sites in the frontal cortex of young adult rats is the first demonstration of long-term regulatory phenomena of brain 5-HT transporters triggered by a physiologic stimulus.