Dopamine and schizophrenia: an analysis of the theory.

The postulated relationship of dopamine to schizophrenia ranks among the most important contemporary theories pertinent to the biological bases of behavior. However, as an examination of the relevant research literature makes clear, the theory has not yet been convincingly validated. This lack of validation is due, in part, to a failure to address the following questions: Is dopamine hyperactivity an etiological and/or a symptom factor in schizophrenia; do laboratory measures used to test the theory truly parallel the relevant clinical phenomena; is attenuated dopamine activity a necessary and/or sufficient condition for remission of schizophrenic symptoms? Analysis of these questions not only provides a departure point for examining the theory, but sets the stage for a reformulation of the theory itself.

Free tryptophan response to intravenous insulin in depressed patients.

Levels of free plasma tryptophan, total plasma tryptophan, and total amino acids were determined at various times after insulin administration in patients with either major depressive disorder or dysthymic disorder and normal control subjects. Prior to insulin administration, there were no significant differences among the three groups in any of the parameters. However, following insulin, free plasma tryptophan levels fell significantly among the patients with major depressive disorder for the first 30 min, but not among normal controls. The rate of decline among the patients with dysthymic disorder was intermediate between those of the patients with major depressive disorder and normal controls. The levels of total tryptophan and amino acids following insulin did not differ significantly among the three groups.

Arylsulfatase A pseudodeficiency-associated mutations: population studies and identification of a novel haplotype.

Pseudodeficiency of arylsulfatase A is characterized by reduction of arylsulfatase A activity without neurodegeneration, making it an important complication when diagnosing metachromatic leukodystrophy. Two DNA substitutions are associated with arylsulfatase A pseudodeficiency. One, 1788A-->G, results in the loss of an N-glycosylated asparagine in the protein, and the second, 2723A-->G, removes the polyadenylation signal site of the mRNA. Previously, the polyadenylation signal site variant was observed only in the presence of the N-glycosylation site variant, although the latter has been reported to occur in the absence of the polyadenylation signal site variant. We investigated the frequencies of these alleles and their linkage disequilibrium in a number of populations and in psychiatric patients. While the N-glycosylation site variant had a high frequency in the Bantu-speaking people from Southern Africa (0.44), the San of Southern Africa (0.22), African Americans (0.37), and Cheyenne Indians (0.375), the polyadenylation signal site variant was absent in these groups. The mutated polyadenylation signal site was found only in the Caucasian groups surveyed. Two Caucasian sibs were identified with the pseudodeficiency polyadenylation signal site variant in the absence of the N-glycosylation site variant, indicating that linkage disequilibrium between the two polymorphisms is not perfect.

Differential response of plasma glucose, amino acids and nonesterified fatty acids to insulin in depressed patients.

Levels of plasma glucose, nonesterified fatty acids and total amino acids at various times after insulin administration were determined in patients with either major depressive disorder or dysthymic disorder and in normal control subjects. For the first 30 min following insulin administration, the rate of change in glucose levels was significantly less among the patients with major depressive disorder than among either the patients with dysthymic disorder or the normal control subjects. However, during the same time period, the rates of decline in nonesterified fatty acids and total amino acids were indistinguishable among the three subject groups. Therefore, the insulin resistance in terms of glucose levels that is observed in patients with major depressive disorder is not generalized to other substances affected by insulin.

Attention deficit disorder and pathological gambling.

To examine the possibility that pathological gambling is related to the deficits in impulse control associated with attention deficit disorder, 14 pathological gamblers and 16 controls were administered questionnaires concerning their childhood behaviors. These self-reports indicated a strong correlation between pathological gambling and childhood behaviors related to attention deficit disorder.

Association of a serotonin transporter gene promoter polymorphism with harm avoidance behaviour in an elderly population.

A polymorphic 44-nucleotide insertion/deletion in the promoter region of the serotonin transporter gene (5-HTTLPR) has been shown to affect the level of expression of the serotonin transporter protein. An association between anxiety-related behavioural traits and the short form of the 5-HTTLPR has been reported. We determined the 5-HTTLPR genotype in genomic DNA samples from 84 subjects (47 Parkinson's disease patients and 37 controls) with a mean age of 67.4 years. The TPQ of Cloninger was used to obtain values for harm avoidance (HA), reward dependence and novelty seeking for all subjects. Analysis of variance showed a significant influence of the s-allele of the 5-HTTLPR on HA in both subject groups, with no significant interaction between diagnosis and genotype. Subjects with the l/l-genotype had significantly lower mean HA scores than the l/s subjects (P < 0.04) and s/s subjects (P < 0.003). A linear change in HA with genotype was observed, indicating a gene dose effect of the 5-HTTLPR s-allele on this personality dimension. Based on these findings it is suggested that there may be increased influence of the 5-HTTLPR short allele on anxiety-related traits during aging.

Galactose biosensors using composite polymers to prevent interferences.

A biosensor using a composite polymer to prevent interferences was used in a flow injection analysis system for the detection of galactose in human plasma. The biosensor consisted of galactose oxidase immobilized on a platinized carbon electrode that had been modified with a composite polymer. The composite polymer showed improved selectivity to hydrogen peroxide compared with either of its individual polymeric components, Nafion and a copolymer of diaminobenzene and resorcinol. The composite polymer minimized the effect of possible interference from urate, ascorbate, and acetaminophen. This analytical system had a minimum detection limit of 50 microM, linearity to 6 mM, a storage stability of greater than 30 days, and a high sample throughput (approx. 120 samples/h).

A novel arylsulfatase A protein variant and genotype in two patients with major depression.

A new, 'diffuse, multiple banding', electrophoretic variant of arylsulfatase A protein was found in two patients with major depression. Protein analyses showed that this variant and the normal enzyme differed in amino acid sequence and/or post-translational modifications unrelated to phosphate groups and oligomannose glycans. Analysis of the arylsulfatase A genes from a subject with the new variant identified three mutations; one gene had the two mutations associated with arylsulfatase A pseudodeficiency, and the other had a G to T transversion which changes a tryptophan to cysteine in the protein. These mutations result in an arylsulfatase A protein heteromer with diffuse electrophoretic banding. The possible association of these mutations with major depression is discussed.

The interaction of lead exposure and arylsulfatase A genotype affects sulfatide catabolism in human fibroblasts.

Lead exposure causes cognitive and behavioral deficits in some affected children. We propose that a contributing mechanism for the neurological damage is that lead induces critically low levels of arylsulfatase A (ASA) at sensitive stages of nervous system development. It is hypothesized that the combined effects of a single nucleotide polymorphism (SNP) in human ASA which results in reduced levels of the enzyme, and lead concentrations which decrease ASA activity culminate in cellular enzymic activity that is below a critical threshold required for the maintenance of normal nervous system function. Human fibroblasts grown in the presence of 20 microM lead acetate exhibit a more than 60% decrease of cellular ASA enzyme protein. Lead treatment of cells from individuals with the SNP(s) of pseudodeficient ASA, but not those from subjects with the normal gene, results in a significant decrease in ability of the cells to desulfate sulfatide, the substrate of ASA. The decrease in the degree of sulfatide catabolism is consistent with possible enhanced lead-induced neurobehavioral effects in individuals homozygous for the pseudodeficiency polymorphism(s) of ASA.

Uric acid level increases in humans engaged in gambling: a preliminary report.

The effect of gambling and gaming on plasma levels of uric acid was studied. Blood samples were obtained from normal subjects while they gambled for money or while they played checkers without betting. There was an interaction of time and activity reflecting primarily an association of increased uric acid levels during gambling over time, compared with gaming and relaxation. This indicates that gambling can increase plasma levels of uric acid.

Rat brain and serum lithium concentrations after acute injections of lithium carbonate and orotate.

Eight hours after intraperitoneal injections of 1.0, 2.0, and 4.0m equiv Li kg-1, the serum and brain lithium concentrations of rats were significantly greater after lithium orotate than after lithium carbonate. While little serum lithium remained at 24 h after injection of 2.0 m equiv kg-1 lithium carbonate, two-thirds of the 2 h serum lithium concentration was present 24h after lithium orotate. Furthermore, the 24 h brain concentration of lithium after lithium orotate was approximately three times greater than that after lithium carbonate. These data suggest the possibility that lower doses of lithium orotate than lithium carbonate may achieve therapeutic brain lithium concentrations and relatively stable serum concentrations.

Relation between serum uric acid and blood pressure in adolescents.

In adults, serum uric acid is positively associated with blood pressure levels. It is also a predictor of the development of hypertension in normotensive adults. The purpose of this study was to examine the relation of serum uric acid to systolic and diastolic blood pressure in adolescents. The data, from Cycle III of the National Health Examination Survey, consisted of a national probability sample of 6768 youths, 12-17 years old, in the United States. With age, height, weight, and sexual maturity controlled, serum uric acid significantly predicted blood pressure in adolescents. This relationship of uric acid and blood pressure was evident in male, but not female, adolescents. In association with findings from adult studies, these results indicate that uric acid levels may be useful indicators of adolescents at risk for hypertension.