Richard J. Wurtman - US grants

Administration of the artificial sweetener aspartame (L-aspartyl-phenylalanylmethylester) in fairly large doses (200 mg/kg) to rats elevates brain levels of phenylalanine and, especially, tyrosine. These effects are enhanced if animals eat a carbohydrate concurrently (because the resulting secretion of insulin lowers plasma levels of other large neutral amino acids that compete with phenylalanine and tyrosine for brain uptake). We propose a program of research to examine some of the physiological and behavioral consequences of these brain changes, and to assess the likelihood that similar changes occur in human subjects. We believe that this research is important both because of the widespread and growing use of the sweetener and because it may yield useful information about certain basic-science questions (e.g., the equivalence of amino acid doses for humans and rats; the extents to which techniques commonly used to measure blood-pressure changes in rats have their own affects on the whether aspartame can modify the synthesis and release of catecholamines from physiologically-active neurons; 2) comparing the dose-response relationship for plasma amino acid levels and ratios in rats and humans given aspartame alone, or with particular dietary carbohydrates. (For example, if - as seems likely - brain phenylalanine levels can be predicted from the ratio of plasma phenylalanine to the sum of other LNAA, then it should be possible to determine which aspartame dose, given to a human, is likely to elevate brain phenylalanine to the same extent as a certain ose given to rats.); 3) extending our preliminary observations showing that aspartame (200 mg/kg) can lower blood pressure in hypertensive rats (presumably by raising brain tyrosine); and, 4) determining whether aspartame doses that probably alter brain tryptophan and serotonin levels affect subsequent food intake and nutrient choice.

In the four years since we and the others first observed that consumption of choline or lecithin raised brain acetylcholine levels in rats, these neurotransmitter precursors have been used successfully to treat one psychiatric disease, tardive dyskinesia, and tried in a few patients with other diseases (Mania; memory disorders). We are undertaking a program of research, involving humans and experimental animals, designed to increase our fundamental understanding of lecithin's effects, and to apply this knowledge to clinical problems. One set of studies explores the fate of ingested lecithins, and examines the contributions of various choline sources to blood choline; a second studies the origins of brain choline (e.g., carrier-mediated uptake from the blood; endogenous lecithin biosynthesis); a third examines some psychopharmacological effects of choline (e.g., on animal behaviors; its interactions with lithium and with opiate agonists; relations between choline's effectiveness and neuronal firing rates; possible feedback regulation of elective lecithin consumption). Clinical experiments examine the clinical utility of choline/lecithin in psychiatric diseases (pilot studies on mania and on memory disorders); the effects of various phosphatide preparations (e.g., egg vs soy lecithin) on blood choline levels in normal subjects; and the quantities of dietary choline needed to induce daily rhythms in plasma choline.

Examines the acute behavioral, EEG and hormonal changes that occur when humans are exposed to the physiological doses of the hormone at noon, early evening and late evening. This will test the relationship between efficacy of melatonin doses and circadian time. Levels of alertness and psychomotor performance will be continuously assessed. EEG patterns during 2 hour sleep test will be registered and blood samples will be taken via indwelling venous catheter for determination of serum melatonin levels.

To compare carbohydrate-rich and protein-rich weight reduction plans on the long-term efficacy of Dexfenfluramine on weight loss. Subjects are to be treated with Redux for 12 months and consume twice daily a high carbohydrate beverage designed to increase brain tryptophan uptake or consume a control, protein-rich beverage that will inhibit brain tryptophan uptake. Weight loss will be monitored for 12 months.

To determine whether sleep disturbances are associated with nocturnal melatonin secretion. To characterize the effects of augmenting circulating melatonin levels on sleep, mood, performance, cortisol secretion, plasma cAMP, and cGMP concentrations and body temperature.

To monitor blood dopamine and serotonin levels, among obese women treated for 8 weeks with phentermine hydrochloride.

To study Choline uptake and metabolism in the brain in Alzheimer's Disease.

To monitor weight loss and blood pressure among normotensive obese women treated for 8 weeks with phentermine hydrochloride who are consuming a protein-rich or protein-poor dietary supplement twice daily.

weight loss; human therapy evaluation; reducing diet; serotonin; dietary carbohydrates; therapy compliance; patient oriented research; clinical research; human subject; nutrition related tag;

premenstrual syndrome; menstrual cycle; personal log /diary; clinical research; female; health surveys; human subject;

lactalbumin; dietary aminoacid; nutrient interaction; blood chemistry; tryptophan; dietary proteins; dietary carbohydrates; clinical research; human subject; nutrition related tag;

uridine; dietary constituent; purine /pyrimidine metabolism; pancreatic islet function; insulin; nutrient interaction; seafood; blood chemistry; diet; dietary carbohydrates; clinical research; human subject; nutrition related tag;

human therapy evaluation; pain; lactalbumin; diet therapy; menstrual cycle; premenstrual syndrome; dietary constituent; emotions; tryptophan; appetite; dietary proteins; dietary carbohydrates; clinical research; human subject; female; nutrition related tag;