Long-term Consequences of Early Undernourishment on the Activation of Brain Serotonin Synthesis in the Rat: Effect of Nutritional Recovery during the Period of Nursing.

In the present study we report that the undernourished rats during fetal life submitted to a neonatal recovery regime had a return to normal metabolic and physical growth conditions during the nursing period, and that their food consumption was more than controls, from weaning until adult age. However, in spite of the metabolic and physical recovery of the gestational undernourished rats, the activity of brain tryptophan-5-hydroxylase (TrpOH) remained elevated accompanied by an increase in the concentration of the neurotransmitter, serotonin (5-HT). Besides, the current observation confirms and extends to previous results, that an increase in brain 5-HT content, in L-tryptophan (L-Trp) concentration and in the activity of TrpOH, in undernourished rats occurs not only during gestation and lactation periods, but it lasts until adulthood. The increase in the activity of TrpOH observed during the fetal stage and continuing to postnatal life in undernourished rats seems to be secondary to an increased transport of plasma L-Trp to their brain. These findings suggest the hypothesis that the mechanism of accelerated synthesis of brain 5-HT in the adult nutritionally recovered animals, may not depended on the increased availability of free plasma L-Trp observed in the undernourished rats, but might be due to a specific change in the TrpOH structure, supported by previous results showing different kinetic and phosphorylating properties. Our observations also suggest that the increased food intake in the recovered animals imply changes in feeding behavior possibly related to the altered serotonin brain neurotransmission.

Nutritional recovery does not reverse the activation of brain serotonin synthesis in the ontogenetically malnourished rat.

In the present work we confirm that gestational malnutrition effects body and brain composition and results in an activation of the synthesis of the brain neurotransmitter 5-hydroxytryptamine. These results also demonstrate more activity of the rate-limiting enzyme tryptophan hydroxylase in the malnourished fetal and postnatal brain. However, the activity of this enzyme remains increased in the brain of nutritionally recovered animals accompanied by an increase in the synthesis of 5-hydroxytryptamine. We therefore suggest that, in the nutritionally recovered animal, the mechanism of activation of this biosynthetic path in the brain may be not dependent on the increased availability of free L-tryptophan observed in malnourished animals, but might be due to a specific change in the enzyme complex itself. This hypothesis is supported by the fact that plasma free and brain L-tryptophan return to normal in the recovered animal.

Early nutritional changes modify the kinetics and phosphorylation capacity of tryptophan-5-hydroxylase.

Gestational malnutrition induces an acceleration of the serotonin biosynthetic pathway in the developing brain with an increase in brain L-tryptophan (L-Trp), tryptophan-5-hydroxylase (TrpOH) activity and serotonin content. In the present work we report results on the possible mechanism of TrpOH activation. Kinetic experiments were done with different L-Trp concentrations in the rat brain at different ages. Also various phosphorylating conditions of the enzyme were tested in order to compare its activation in developmentally malnourished and normal brains. The results showed lower Km values and no changes in the Vmax in the malnourished as compared to controls. Interestingly, in the malnourished group, TrpOH showed an increased activity under the phosphorylating conditions employed. We propose that in the activation of brain TrpOH by developmental malnutrition, not only is an elevation of L-Trp involved, but also a change in the enzyme itself reflected in a higher affinity for L-Trp and in a greater response to phosphorylation. This allows us to propose the possibility that early chronic malnutrition induces structural changes in the enzymatic molecule.

Newborn humans and rats malnourished in utero: free plasma L-tryptophan, neutral amino acids and brain serotonin synthesis.

In the present study we report results concerning 5-hydroxytryptamine (5-HT) metabolism in two groups of small for date (SFD) human babies (gestational age 36 and 3 weeks), who suffered intrauterine nutritional restriction. A complementary study in the brain of rat fetuses with two types of intrauterine deprivation, in which brain L-tryptophan (L-Trp), tryptophan-5-hydroxylase (T5-H) activity and 5-HT content were determined on days 17, 19 and 21 of gestation. The same parameters studied prenatally were followed in both species during the immediate postnatal period. In the SFD babies the results were: (a) the free fraction of plasma L-Trp was significantly elevated; (b) plasma neutral amino acids were not substantially modified; (c) the bound fraction of L-Trp and plasma proteins were significantly low, as compared to controls. In the fetal brain of intrauterine malnourished rats, L-Trp, activity of T5-H and 5-HT content, were significantly elevated, since day 17, as related to normal littermates. These alterations in 5-HT metabolism persisted during the early postnatal period in both species. Elevation of the free fraction of plasma L-Trp in early malnourished SFD human babies suggest an increased transport of this amino acid to the brain with a possible enhancement of serotonin synthesis, during a critical period of brain differentiation.