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Biomedical subjects

R D Todd

Publications and source records attributed to R D Todd.

At least 91 records · Page 5Linked to original sources
PubMed1989

Complex responses activated by ibotenate in postnatal rat hippocampal neurons.

The actions of the excitatory amino acid ibotenate were investigated in postnatal rat hippocampal neurons. In neurons voltage clamped at negative membrane potentials using low-chloride internal solutions, ibotenate responses consist of an inward cationic current and two outward currents. The inward current is inhibited by 2-amino-5-phosphonovalerate (APV), a selective N-methyl-D-aspartate (NMDA) antagonist. The two outward currents consist of a picrotoxin and bicuculline-sensitive chloride current and a slowly developing calcium activated potassium current. The bicuculline sensitive current appears to be the product of contamination of ibotenate samples with the gamma-aminobutyric acid (GABA) agonist muscimol and not the result of a direct action of ibotenate.

2-Amino-5-phosphonovalerate↗
PubMed1989

Cloning of ligand-specific cell lines via gene transfer: identification of a D2 dopamine receptor subtype.

Using rat genomic DNA, we have established a transfected mouse fibroblast cell line that expresses a spiperone binding site with the pharmacological characteristics of a D2 dopamine receptor. The expressed D2 receptors are the product of a gene that is distinct from that reported by Bunzow et al. [Bunzow, J. R., Van Tol, H. H. M., Granoly, D. K., Albert, P., Salon, J., Christie, M., Machida, C. A., Neve, K. A. & Civelli, O. (1988) Nature (London) 336, 783-787]. Flow cytometry with the Ca2+-sensitive dye indo-1 demonstrated that activation of the expressed D2 sites resulted in increases in intracellular calcium that were dependent on the influx of external Ca2+. These general cloning procedures should be applicable to the production of cell lines expressing a variety of genes for which only functional assays are available.

Animals↗
PubMed1988

Ascorbate modulates 5-[3H]hydroxytryptamine binding to central 5-HT3 sites in bovine frontal cortex.

Ascorbate is present in millimolar concentrations in mammalian brain and can be released from cellular stores by membrane depolarization. We report here that physiologically relevant concentrations of ascorbate modulate 5-[3H]hydroxytryptamine ([3H]5-HT) binding to bovine frontal cortex membranes. Under conditions where [3H]5-HT binding is reversible and saturable, ascorbate causes a concentration-dependent increase in the affinity of [3H]5-HT for central 5-HT3 binding sites. At pH 7.4, increasing ascorbate from 0 to 5.7 mM changes the equilibrium affinity constant (KD) of binding to 5-HT3 sites from 125 nM to 30 nM, without affecting binding site number. These ascorbate-induced effects are pH dependent. At pH 7.1 binding to central 5-HT3 sites is essentially eliminated in the presence of ascorbate. These studies suggest that ascorbate and hydrogen ion concentration interactions may modulate serotonergic function.

Animals↗
PubMed1988

Are the neurodevelopmental effects of gonadal hormones related to sex differences in psychiatric illnesses?

There are large sex differences in the incidence of many psychiatric diseases. The bases for these sex differences are probably complex and are likely to involve the interaction of both social and biological factors. Probable social factors include child rearing practices, personal expectations and lifestyles, and societal institutions. Biological factors would likely include genetic effects, hormonally mediated neurodevelopmental effects and hormonally mediated neuroregulatory effects. This paper focuses upon the developmental effects of gonadal hormones. The sex differences observed in the neuroanatomy and behavior of nonhuman mammals are reviewed. The instances in which developmental exposure to gonadal hormones has been demonstrated to be involved in establishing these sexual dichotomies are surveyed. The molecular mechanisms by which differences in prenatal and early postnatal levels of gonadal hormones may generate such sex differences are examined. Sex differences in human neuroanatomy and cognitive function are discussed. Finally, we speculate on ways in which similar hormonal mechanisms might act to influence psychiatric disorders.

Animals↗
PubMed1988

The importance of regressive changes in the development of the nervous system: towards a neurobiological theory of child development.

In this paper we propose that theories of early personality development be revised to consider knowledge of neurodevelopment. Research findings are reviewed that have established the presence of regressive changes in the normal development of the brain. These regressive changes, consisting of neuronal death and process and synapse elimination, are theoretically linked to three precursors of personality: sex differences, temperamental traits and perceptual-motor coordination. Evidence supporting these hypotheses is provided from studies examining how the effects of genetic, environmental, and experiential factors on brain development may determine the development of these personality features.

Animals↗
PubMed1987

Multiple high-affinity [3H]serotonin binding sites in human frontal cortex.

High-affinity [3H]serotonin (5-hydroxytryptamine, 5-HT) binding sites from human frontal cortex can be divided into at least 3 pharmacological subtypes (5-HT1A, 5-HT1B and 5-HT3) based on affinity for [3H]serotonin and spiperone. All 3 sites are solubilized by 3% Triton X-100, 1% Tween-80 and can be enriched by serotonin-linked-Sepharose 4B affinity chromatography. However, 5-HT3 sites are more sensitive to heat inactivation, long-term storage, and sulfhydrylalkylation. The pharmacological profiles are distinct for the spiperone-insensitive 5-HT1B and 5-HT3 sites in both human and bovine cortex. In addition, evidence is presented for the existence of a novel, low concentration [3H]serotonin binding site in human cortex.

Aged↗
PubMed1987

A thermodynamic study of 5-[3H]hydroxytryptamine binding to human cortex membranes.

Kinetic and equilibrium measurements of [3H]-serotonin (5-hydroxytryptamine) binding to human frontal cortex membranes have been made between 4 and 30 degrees C. The effects of spiperone and ascorbate on binding have also been determined. Under the conditions used, binding was saturable and reversible. Affinity constants derived from kinetic and equilibrium data were comparable. Serotonin binding to several sites had substantial enthalpic as well as entropic components.

Cell Membrane↗
PubMed1986

Pervasive developmental disorders and immunological tolerance.

A wide range of studies in man and other species suggest that early compromise of immunological tolerance (both maternal-fetal and self) may lead to severe and varied cognitive deficits. This article briefly reviews what is known of the genesis and maintenance of normal tolerance and current ideas on pathological deviances in tolerance. These ideas are discussed in relation to risk factor, family, twin, biochemical, anatomical, and immunological studies of pervasive developmental disorders (particularly infantile autism). A range of immunological injury hypotheses for the genesis of the pervasive developmental disorders are considered and technical problems in deciding among them are presented.

Autistic Disorder↗
PubMed1985

Demonstration of inter- and intraspecies differences in serotonin binding sites by antibodies from an autistic child.

Serotonin (5-HT) binding sites from bovine and rat cerebral cortex membranes share pharmacological properties that allow both to be subclassified by the same criteria. We show here that [3H]5-HT binding sites from human cortex also possess pharmacological properties that follow the same subclassification scheme as for bovine and rat cortex. In addition, we show that solubilized 5-HT1 and 5-HT3 sites from all three species have an s20,w value of 3.4. Despite these similar pharmacological and physical characteristics, we can demonstrate antigenic differences between receptor types and species. Human 5-HT1A sites can be distinguished from human 5-HT1B, 5-HT2, and 5-HT3 sites and from equivalent sites in rat and bovine cortex. The anti-human 5-HT1A antibodies were discovered in the blood of an autistic child and may have clinical or etiologic significance for this disorder.

Animals↗
PubMed1983

Presence and stoichiometry of two forms of subunit 6 of the mitochondrial ATPase complex of yeast.

One of the mitochondrically coded components of the yeast mitochondrial ATPase complex (subunit 6) can be resolved into two components on certain polyacrylamide gels in the presence of sodium dodecyl sulfate. Purification of the ATPase complex from commercially processed yeast as well as immunoprecipitation of the holo-enzyme from cells labeled in vivo with 14C-labeled amino acids demonstrate that both forms of subunit 6 are physically associated with the assembled enzyme and present in two copies each per complex. One-dimensional papain-generated peptide maps of the two components are identical except for the mobility of a single fragment. It is concluded that the two components of subunit 6 are different forms of a single protein and are present on an average of two copies each per complex.

Adenosine Triphosphatases↗
PubMed1983

Solubilization and characterization of high-affinity [3H]serotonin binding sites from bovine cortical membranes.

High-affinity [3H]serotonin binding activity has been solubilized from bovine cerebral cortical membranes by using Triton X-100, Tween-80, and octyl-beta-D-glucopyranoside. This mixture of detergents solubilizes the high-affinity [3H]serotonin binding activity present in crude membrane preparations with retention of 75-90% specific binding. The detergent mixture was chosen because it can easily be removed from the solubilized fraction by dialysis and polystyrene bead adsorption, thus permitting further purification and isolation of the binding sites. Saturation analysis reveals multiple components of high-affinity [3H]serotonin binding. In crude bovine cortical membranes, at least two binding components are present. A higher-affinity binding component, as defined from curvilinear Scatchard plots, has a Kd for [3H]serotonin of 1-3 nM, whereas a lower-affinity component has a Kd of 10-20 nM. In the solubilized preparation, only a single class of binding sites is apparent, with a Kd of 50-100 nM. Removal of detergents by dialysis and polystyrene bead adsorption results in restoration of the curvilinear Scatchard plot with apparent Kds similar to those observed in crude membrane preparations and with increased Bmax values for each component. [3H]Serotonin binding activity in the solubilized preparation is stable to Sephacryl S-300 column chromatography and to glycerol gradient sedimentation. Saturation analysis of the peak binding fractions from both these procedures once again yields curvilinear Scatchard plots, indicating that the multiple high-affinity binding components are preserved and migrate together. The molecular weight, Stokes radius, and frictional coefficient of the binding site(s) have been calculated. After detergent removal the solubilized material shows many of the characteristics usually attributed to S1 receptors, such as high affinity for [3H]serotonin and its analogs and low affinity for serotonin antagonists.

Animals↗
PubMed1983

Ventricular arrhythmias induced by doxepin and amitriptyline: case report.

A case is described of ventricular arrhythmias associated with doxepin and amitriptyline treatment in a patient with preexisting heart disease. A significant correlation was found between the occurrence of premature ventricular depolarizations and serum levels of both antidepressants.

Amitriptyline↗
PubMed1982

Determination of morphine in cerebrospinal fluid and plasma by high-performance liquid chromatography with electrochemical detection.

Two methods for the extraction of morphine from cerebrospinal fluid or plasma with quantitation by high-performance liquid chromatography with electrochemical detection were compared for accuracy, precision and ease of preparation. One procedure was a standard extraction procedure and the other utilized a commercially available liquid-liquid extraction column. Both methods produced linear calibration curves over the concentration range of 1-200 ng/ml with coefficients of correlation of 0.999. Since the electrochemical detector is capable of detecting 20 pg of morphine, biological samples as small as 0.1 to 0.4 ml can be quantified with an average relative precision of 4.1 +/- 3.9% over the concentration range 1-200 ng/ml. The potential clinical importance of the assay is demonstrated using a time course distribution study of morphine in the cerbrospinal fluid and plasma of a Rhesus monkey.

Animals↗
PubMed1981

Localization of unassembled subunits of the mitochondrial ATPase in an assembly-defective yeast nuclear mutant.

The yeast nuclear mutant, pet 936, has previously been shown to be defective in the assembly of a functional mitochondrial ATPase (Todd, R. D., McAda, P. C., and Douglas, M. G. (1979) J. Biol. Chem. 254, 11134-11141). In the present report, trypsin degradation and subunit-specific antibody binding have been used to localize subunits 1, 2, and 3 external to or associated with the outer aspect of the inner mitochondrial membrane in the mutant strain. A similar population of unassembled subunits was found in the parental strain as well. Isotope dilution experiments are compatible with those unassembled subunits being normal intermediates in the assembly pathway of the ATPase complex which are blocked from transport across the inner mitochondrial membrane in the mutant, pet 936.

Adenosine Triphosphatases↗
PubMed1981

A model for the structure of the yeast mitochondrial adenosine triphosphatase complex.

Monodisperse, Triton-solubilized ATPase complex was treated with the reversible protein-protein cross-linker dithiobis(succinimidyl)propionate under conditions where only intracomplex cross-links were formed. The resulting products were analyzed by two-dimensional sodium dodecyl sulfate-acrylamide slab gel electrophoresis under reducing and oxidizing conditions. Using the observed major subunit-subunit cross-links and the previously published subunit stoichiometries (Todd, R., Griesenbeck, T., and Douglas, M. (1980) J. Biol. Chem. 255, 5461-5467), a model of the ATPase complex was constructed. The model is a closed structure which could be formed by self-limited assembly of the subunits. The model also has the novel features of a pseudo-mirror symmetry and clustering of mitochondrially and nuclearly coded subunits into two different domains.

Adenosine Triphosphatases↗