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Biomedical subjects

R Dawson

Publications and source records attributed to R Dawson.

175 records · Page 10Linked to original sources
PubMedDate not supplied

Endogenous glutamate release from frontal cortex of adult and aged rats.

Glutamate (GLU) is a major excitatory neurotransmitter in the frontal cortex. Alterations in GLU neurotransmission are present in a number of neurodegenerative diseases, however, little is known about the normal aging process of GLU utilizing neurons. GLU release, uptake and content were examined in the frontal cortex of adult (6 months old) and aged (24 months old) male, Fisher 344 rats. These markers were used to assess the functional integrity of intrinsic and extrinsic GLU utilizing pathways innervating the frontal cortex. Basal- and potassium- (56 mM) evoked GLU release from brain slices of aged rats were not significantly different from that of adults. Kainic acid (1.0 mM) failed to significantly augment basal or potassium-stimulated GLU release in the frontal cortex of either aged or adult rats. Uptake of [3H] GLU into brain slices was also unaltered as a function of age. In contrast, GLU content was decreased 17% in the frontal cortex of aged rats when compared to the adults. These results suggest that the functional integrity of GLU utilizing nerve terminals in the frontal cortex is maintained in 24-month-old Fisher 344 rats. The decrease in GLU content may reflect a generalized neuronal loss or a defect in neuronal and/or glial GLU metabolism in the metabolic compartment.

Aging↗
PubMedDate not supplied

Kainic acid-induced seizures in aged rats: neurochemical correlates.

This study was conducted to assess the functional integrity of the kainate receptor-mediated seizure response in aged rats. Kainic acid was administered systemically to aged female Long-Evans (LE) rats and aged male F344 rats and the proconvulsant actions of kainic acid was compared to adult controls. The effects of kainic acid on brain regional content of monoamines and amino acids was also determined in the aged female LE and adult control rats. The latency to full clonic-tonic seizures was significantly reduced in aged female LE rats, and the number of seizures was significantly increased above that of the controls. There was increased mortality and a reduction in the latency to exhibit wet dog shakes in the aged F344 rats. Studies were also conducted to evaluate the role of ovarian hormones, route of administration, and dose of kainic acid in mediating the enhanced proconvulsant actions of kainic acid in aged rats. The neurochemical studies suggested that kainic acid significantly enhanced the release of ASP, GLU, and norepinephrine (NE) in the aged rats exhibiting clonic-tonic seizures. The adult rats given the same dose of kainic acid (15 mg/kg, IP) did not exhibit any significant change in brain content of monoamines or amino acids except for a reduction in mediobasal hypothalamic NE. An in vitro study was also conducted using brain slices from adult and aged F344 and it was found that aged rats released significantly more ASP than adults in response to kainic acid. These neurochemical findings were discussed in relation to previous studies of age-related alterations in excitatory amino acids (EAAs) and the role of EAA and NE in modulating limbic seizures. This study has clearly demonstrated that aged rats may be more susceptible to the excitotoxic action of EEAs acting through kainetic receptors.

Aging↗
PubMedDate not supplied

Age- and dose-dependent effects of neonatal monosodium glutamate (MSG) administration to female rats.

The age- and dose-dependent effects of neonatal MSG were evaluated in pre- and postpubertal female rats. The neurotoxic action of MSG was assessed by examining monoamine content in microdissected regions of the mediobasal hypothalamus. MSG was administered at a dose of 4 mg/g on postnatal days 2 and 4 (MSG-Lo) or on postnatal days 2, 4, 6 and 8 (MSG-Hi). MSG-Hi treatment significantly reduced dopamine (DA) content in the arcuate nucleus (ANH) and lateral median eminence (LME) on postnatal day 21 when compared to NaCl-injected controls. DA content relative to controls was not altered in the ANH or LME postnatal or postnatal day 60 in MSG-Hi, however, norepinephrine (NE) was significantly (p less than 0.05) decreased on both postnatal day 21 and 60 in the LME. MSG-Lo treatment significantly (p less than 0.05) reduced ANH NE content on postnatal day 60 compared to controls. Both MSG-Hi and MSG-Lo treatment increased 5-hydroxyindoleacetic acid content in the preoptic area (POA) on postnatal day 60 relative to the controls. Developmental changes independent of MSG treatment were noted in the hypothalamus. DA and 3,4-dihydroxyphenylacetic acid (DOPAC) content in the POA were 2-3-fold higher on postnatal day 21 compared to postnatal day 60. In contrast, DA content increased with age in the ANH, LME and medial ME. NE content in the ANH increased as a function of age in controls, but not in MSG-treated rats. The effects of MSG treatment on the postnatal development and maturation of neurons in the mediobasal hypothalamus were discussed in relation to the direct neurotoxicity of MSG.

3,4-Dihydroxyphenylacetic Acid↗
PubMedDate not supplied

Course of treatment received by depressed patients.

Using data from an observational study of affective disorders, we describe the rates of transition among levels of antidepressant treatment for subjects with Major Depressive Disorder (MDD), and relate these changes to changes in clinical status. We report on the treatment received during the first 10 years of follow-up in the Collaborative Depression Study by 555 patients with a diagnosis of MDD of at least one month's duration. This work extends the initial examination of treatment received during the first eight weeks after entry into this study that showed depressed patients to be on low levels of treatment. Multiplicative intensity models which generalize survival analysis models were used to analyse these data. Description of the course of treatment of these depressed patients shows that low levels of treatment persist for these patients across subsequent episodes, and that these episodes, like the index one, are characterized by extended time in a symptomatic subcriterion state after acute symptoms have improved. These long-term descriptions of treatment support the initial hypothesis that these CDS patients were undertreated. The long-term tendency toward undertreatment seems to persist even as newer treatments become available and widely accepted in practice.

Acute Disease↗
PubMedDate not supplied

Attenuation of trimethyltin-evoked glutamate (GLU) efflux from rat cortical and hippocampal slices.

Trimethyltin (TMT) is a toxic alkyltin that produces neuronal necrosis in the CNS. TMT stimulates the efflux of the excitatory amino acid glutamate (GLU) from rat cortical slices. This release is concentration dependent, partially calcium dependent, but not inhibited by calcium channel blockers or a NMDA antagonist. In the present study the compounds furosemide, bumetanide, 4,4'-diisothiocy-anatostilbene-2,2'-disulfonic acid (DIDS), and DL-threo-beta-hydroxyaspartic acid (HAA) were tested for their ability to attenuate TMT-stimulated GLU efflux from rat cortical and hippocampal slices. Furosemide (1 mM) reduced the TMT-induced GLU efflux in cortical slices and hippocampal slices, but bumetanide (0.1 mM) had no effect on TMT-induced GLU efflux. DIDS (1 mM) demonstrated a trend toward decreasing GLU efflux from TMT stimulation in both the cortex and hippocampus, but this reduction was not significant. However, DIDS was able to prevent the decrease in intracellular GLU content produced by TMT in both the cortical and hippocampal slices. HAA (1 mM) increased the net GLU efflux in both cortical slices and hippocampal slices, and produced a significant depletion of the glutamate content of the slices. Taurine efflux was stimulated by TMT treatment but was not blocked by the chloride transport inhibitors. These data suggest that cell swelling-induced release of GLU may not be directly involved in TMT-induced GLU efflux, and that TMT does not appear to elicit GLU efflux by a mechanism involving reversal of the GLU transporter.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMedDate not supplied

Neurochemical and neurobehavioral effects of neonatal administration of beta-N-methylamino-L-alanine and 3,3'-iminodipropionitrile.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is characterized by a loss of motor neurons in the spinal cord, brain stem, and cortex. The present study examined the neurochemical and neurobehavioral consequences of the neonatal administration of IDPN and BMAA, two neurotoxins previously considered as experimental models of ALS. Sprague-Dawley rat pups (male and female) were injected SC with IDPN or BMAA. The following treatment groups (n = 5-14 per group) were studied; IDPN [100 mg/kg on postnatal days (PNDs) 2, 4, and 6], BMAA-A (500 mg/kg PND 5 only), BMAA-B (500 mg/kg PND 2 and 5), and BMAA-C (100 mg/kg PND 2 and 5). Neurobehavioral testing was performed and the rats were sacrificed at 101 days of age. Monoamine and amino acid content was measured by HPLC in brain regions and the spinal cord. IDPN treatment impaired the righting reflex and decreased forepaw suspension times. BMAA-A and BMAA-B males exhibited an increase in open field behavior. The hindlimb splay of BMAA-A females was increased. Other significant behavioral and endocrine effects were also seen with neonatal IDPN or BMAA treatment. IDPN females had increased spinal cord content of norepinephrine (NE), serotonin, and 5-hydroxyindoleacetic acid (5-HIAA). IDPN males had no alterations in spinal cord content of NE or Glu, but serotonin and 5-HIAA content were increased. BMAA-A and BMAA-B males also had elevated spinal cord 5-HIAA content whereas females were unaffected. Glu and Asp content in the spinal cord was elevated in the female BMAA-C group. Monoamines were also altered in the cerebellum, mediobasal hypothalamus, and hippocampus by IDPN and BMAA treatment. alpha 2-Adrenergic binding sites were increased in the spinal cord by IDPN and in the cerebellum by BMAA treatment. The results of this study clearly demonstrated that both IDPN and BMAA given neonatally can produce changes in motor function and spinal cord neurochemistry, although the pattern of the effects is both treatment and sex dependent. Neonatal exposure to either IDPN or BMAA resulted in permanent changes in adult neurochemistry that may be related to reorganizational effects induced by toxin-mediated neuroplasticity in developing neurons.

Amino Acids↗
PubMedDate not supplied

Characterization of the synthesis and release of dopamine in LLC-PK1 cells.

The ability of a renal epithelial cell line of porcine origin (LLC-PK1) to synthesize dopamine (DA) from L-dopa and release DA into the culture media was studied. L-Dopa was rapidly taken up by LLC-PK1 cells and converted to DA which was then released into the media. L-Dopa uptake and conversion to DA was competitively inhibited by other aromatic amino acids (Tyr and Phe). Studies were conducted to assess L-dopa uptake, DA synthesis and DA release in LLC-PK1 cells in response to changes in the ionic composition of the Krebs-Ringer bicarbonate (KRB) buffer media and to various drugs known to alter renal transport function. Sodium chloride addition to KRB media resulted in enhanced DNA release into the media that was significantly attenuated by both quinine (1 mM) and benzamil (0.1 mM). Other sodium salts (sodium acetate and sodium phosphate) also enhanced DA release from LLC-PK1 cells. Salts containing chloride (LiCl, NH4Cl, choline chloride) stimulated a greater efflux of DA from LLC-PK1 cells than sodium salts at equimolar concentrations. Osmotic stimuli (sucrose, mannitol and dextran, 50-200 mM) also elicited increased DA release from LLC-PK1 cells into the media but not to the same extent as inorganic salts. DA release (secretion) from LLC-PK1 cells was strongly inhibited (25-50%) by drugs known to be substrates for the renal cation transport system. These studies have characterized extensively the factors that govern and regulate the synthesis of DA from L-dopa and the transport system responsible for the secretion (release) of intracellular DA into the media.

Animals↗
PubMedDate not supplied

A comparison of the fragment constant and molecular connectivity indices models for normalized sorption coefficient estimation.

Fragment constant and molecular connectivity indices models were developed based on the measured normalized sorption coefficient values of 592 chemicals. The two models were compared for precision in terms of their adjusted coefficients of determination and their mean residuals. Model robustness was evaluated and compared using jackknifed mean residuals derived from class-by-class deletion. Results indicated that a relatively greater precision could be achieved using the fragment constant approach compared with the molecular connectivity indices model. The adjusted coefficients of determination of the two models were 0.965 and 0.765 and the mean residuals were 0.366 and 0.440, respectively. Although there were a relatively small number of independent variables involved, the robustness of the molecular connectivity indices model was greater than that of the fragment constant method as far as extrapolation among chemical classes is concerned.

Adsorption↗
PubMedDate not supplied

Prediction of the bioconcentration factor of PCBs in fish using the molecular connectivity index and fragment constant models.

Models based on molecular connectivity index (MCI) and fragment constant (FC) method were developed for prediction of the bioconcentration factor (BCF) for polychlorobiphenyls (PCBs) in fish. The mean residuals for the MCI and FC models were 0.195 and 0.223 log units, respectively. The two models were then compared in terms of their mean residuals. In addition to the chlorine atom substitution number, other important structural features exhibiting a significant influence on the BCFs of PCB congeners were discussed and incorporated to the models. These features include the degree of the ortho-substitution, the presence of chlorine pairs in the three- and five- positions, and the crowding of chlorine atoms on the phenyl ring.

Animals↗
PubMedDate not supplied

Selective neurochemical and histological lesions in rat hippocampus following chronic trimethyltin exposure.

Trimethyltin exerts a unique and selective pattern of toxicity which may be related to the neurochemical innervation of the hippocampus. Rats were chronically administered trimethyltin and the kinetics of neurotransmitter uptake was assessed in hippocampal synaptosomes. Additional rats were prepared for histological examination. Uptake of the endogenous hippocampal amino acid neurotransmitters glutamic acid and gamma-aminobutyric acid showed dose-dependent alterations. Uptake of norepinephrine was not significantly affected. Histopathological analysis indicated differential neuronal loss within classically defined hippocampal cell fields.

Animals↗
PubMedDate not supplied

A behavioral assessment of arcuate nucleus damage after a single injection of monosodium glutamate.

The behavioral and histological consequences of the administration of a single injection of monosodium glutamate (MSG) to neonatal mice, were examined. Profound neuronal loss was evident in the arcuate nucleus of mice administered 4 mg/g MSG on postnatal day 4. Adult MSG-treated mice were obese and hypophagic despite significantly elevated activity levels. In addition, these obese MSG-treated mice maintained their hypophagia even in the presence of a food restriction schedule which resulted in significant weight loss. MSG-treated mice were hypodipsic, but did not differ from controls in their response to adulteration of their drinking water with sodium chloride, saccharin or quinine. These studies demonstrate that a single neonatal injection of MSG is sufficient to produce dramatic behavioral alterations.

Animals↗
PubMedDate not supplied

Naloxone-induced suppression of food intake is potentiated by neonatal administration of monosodium glutamate to mice.

The anorectic potency of naloxone and fenfluramine was evaluated in mice treated neonatally with 4 mg/g of MSG. Naloxone produced a specific and pronounced suppression of food intake in MSG-treated mice, whereas fenfluramine was equipotent in suppressing food intake for both MSG-treated and control mice. Naloxone at doses of 5, 10 and 20 mg/kg was significantly more potent in suppressing food intake in MSG-treated mice when compared to controls. Water intake, however was suppressed to a greater extent in control mice than MSG-treated mice following administration of either naloxone or fenfluramine. These results implicate endogenous opiate systems in the obesity and alterations in food intake regulation exhibited by MSG-treated mice.

Animals↗