The regulation of brain serotonin concentrations by dietary factors affecting brain tryptophan

Abstract

Daily rhythms occur in the concentrations of tryptophan in rat plasma and brain and of serotonin in rat brain. To determine whether these normally-occurring changes in plasma and brain tryptophan could account for the variation in brain serotonin, we injected rats with different doses of L-tryp­tophan and measured the responses of the plasma and brain tryptophan and the brain serotonin pools at various times after injection. A dose of 12.5 mg/kg, given at the time of day when plasma and brain tryptophan levels are normally low­est, produced elevations in plasma and brain tryptophan and in brain serotonin which approached, but did not exceed, peak daily concentrations. Thus, changes in plasma and brain try­ptophan within the normal dynamic range are capable of pro­ducing significant changes in brain serotonin levels. Because the ingestion of carbohydrate produced signifi­cant alterations in plasma and brain tryptophan and in brain serotonin, experiments were performed to test the response of these three pools to the consumption of another constituent of food, protein. Following the ingestion of the same carbohy­drate diet supplemented with casein, 18% dry weight, plasma tryptophan levels became elevated, but brain tryptophan and serotonin concentrations did not change. Inasmuch as protein contains amino acids that compete with tryptophan for trans­port into the brain, the influx of these amino acids along with tryptophan into the circulation following protein inges­tion may have produced an effective inhibition of tryptophan uptake into the brain. Thus, carbohydrate diets containing an amino acid mixture approximating casein in amino acid com­position, but lacking the amino acids thought to compete with tryptophan for transport into the brain (tyrosine, phenylalanine, leucine, isoleucine, and valine), were fed to rats. Follow- ing the ingestion of this diet, plasma and brain tryptophan and brain serotonin and 5-hydroxyindoleacetic acid levels all increased. If animals were fed the amino acid mixture diet lacking aspartate and glutamate (amino acids thought not to compete with tryptophan for transport) instead of the large neutral amino acids, or the complete amino acid mix diet (including the large neutral amino acids), plasma tryptophan concentrations rose, but no increases in brain tryptophan, serotonin, or 5-hydroxyindoleacetic acid occurred. The con­centrations of serotonin and its major metabolite in brain, which appear to be influenced by tryptophan availability to the brain, thus are subject not only to plasma tryptophan levels, but also to the levels of several other amino acids in plasma. These results support the hypothesis that the rate of serotonin synthesis in brain is influenced by tryptophan availability. They demonstrate a remarkable sensitivity of brain serotonin concentrations to changes in brain tryptophan levels within the normal dynamic range. Long-term changes in brain serotonin were also studied in rats consuming a diet containing a naturally-occurring protein very low in tryptophan content (corn protein). In these animals, the plasma and brain tryptophan pools were greatly depressed after five weeks on the diet; brain sero­tonin concentrations were correspondingly decreased. Similar results were obtained in rats eating smaller than normal quantities of a diet containing a protein with normal amounts of tryptophan.