ABSTRACT. Rats implanted with subcutaneous or intraperitoneal osmotic minipumps infusing 0.8-1.25 IU weasel kg/h develop sustained hyperammonemia (range 137-497 pM, controls 88 2 51 pM f SD) for 5-7 days. Glutamine levels are also significantly elevated in plasma (677 f 166 versus 428 f 122 pM) and cerebral cortex (13.2 f 9.8 versus 4.7 f 2.8 nmollmg tissue). Neurobehavioral abnormalities include decreased food intake and increased stereotypic activity. Increased serotonin turnover was suggested by elevated levels of tryptophan and 5-hydroxyindoleacetic acid in cerebral cortex, brain stem, and cerebellum of urease-infused compared to sham-operated animals. There were no changes in norepinephrine or y aminobutyric acid, and there was no correlation between the degree of hyperammonemia or glutaminemia and brain levels of tryptophan or biogenic amines. Animals receiving a tryptophan-deficient diet had significantly lower levels of tryptophan and 5-hydroxyindoleacetic acid in brain regions compared to animals receiving a normal tryptophan intake, under both control and hyperammonemic conditions. Despite the prevention of. increased serotonin flux in hyperammonemic animals receiving a tryptophan-deficient diet, food intake and weight declined and there was increased stereotypic behavior. (Pediatr Res 20: 1310-1315, 1986 Abbreviations Trp, tryptophan Trp (-), tryptophan-deficient diet Trp (+), diet containing adequate Trp HIAA, 5-hydroxyindoleacetic acid 5-HT, serotonin GABA, y-aminobutyric acid NE, norepinephrine ANOVA, analysis of variance ANCOVA, analysis of covariance Inherited deficiencies have been described for each of the five enzymes in the urea cycle. Affected children have hyperammonemia associated with elevations in plasma glutamine and alanine levels. Plasma ammonium levels three to four times normal are associated with anorexia. initabilitv. increased activitv levels. pain.insensitivity, and sleep disturbances. Higher levels'lead td vomiting, lethargy, and coma. Despite effective therapy combin- This work was supported by USPHS Grants MH4069 1 and HD1098 1.ing protein restriction with the stimulation of alternate pathways of waste nitrogen excretion (1) many affected children are mentally retarded and display chronic feeding problems including anorexia and food refusal (2). These behavioral abnormalities also have been associated with increased serotonin metabolism (3). We have previously reported increased cerebrospinal fluid levels of the metabolite of serotonin, HIAA in a 6-yr-old girl with argininosuccinic aciduria who was anorectic and had a sleep disturbance (4). We have since found elevated cerebrospinal fluid HIAA levels (greater than 2 SD above the mean for age) in four of five other anorectic children with urea cycle disorders (Hyman SL, Batshaw ML, unpublished observations).Because the rate limiting step in serotonin synthesis, tryptophan hydroxylase, is not saturated at ambient Trp concentrations, brain serotonin turnover is a function of dietary Trp intake and brain Trp transport (5). Our at...