In response to a chow meal in rats, we observed previously in PVN-VMH dialysates, an increase in serotonin (5-HT) that could be related to satiety or to metabolic consequences of the composition of the meal. Indeed, carbohydrates are admitted to increase 5-HT synthesis while proteins decrease it, but the time course and mechanisms of these effects were not known. For that purpose, pure carbohydrates, proteins, or fats were offered for 30 min and the changes in 5-HT from PVN-VMH dialysates were followed. Carbohydrates (85% starch + 15% sucrose) enhanced 5-HT levels as soon as the first 15 min of feeding, with a maximum 60 min later. Conversely, protein ingestion induced in the second 15 min of the meal, a decrease in 5-HT that lasted 2 h. During a fat meal (lard), 5-HT levels also decreased at the beginning of the meal and remained low during 45 min. The present data reassess the previous theories on the serotonergic effects of specific macronutrient ingestion. The effect of a fat meal on 5-HT levels had never been described so far. The increase in 5-HT in response to a carbohydrate meal is further specified. The 5-HT decrease induced by proteins, in agreement with the previous theories, is better explained now by using pure protein diets and extracellular 5-HT assay. However, all the changes observed start too early to be only metabolic in origin. Other mechanisms may occur, including the release of 5-HT in response to a meal to induce satiety.