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Biomedical subjects

D F Sharman

Publications and source records attributed to D F Sharman.

At least 91 records · Page 5Linked to original sources
PubMed1971

3,4-dihydroxyphenylacetic acid and 4-hydroxy-3-methoxyphenylacetic acid in the mouse striatum: a reflection of intra- and extra-neuronal metabolism of dopamine?

1. The administration of probenecid to mice increased the concentration of 4-hydroxy-3-methoxyphenylacetic acid (HVA) in the striatum, but did not raise the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC).2. After drug treatments which normally increase the concentration of HVA several-fold, inhibition of catechol-O-methyltransferase (COMT) by tropolone greatly reduced the concentration of HVA but resulted in only a small increase in the concentration of DOPAC in the striatum of the mouse.3. These results indicate that HVA and DOPAC do not occur at the same location in the tissue of the striatum and that DOPAC is not normally metabolized to HVA to any great extent in this tissue.4. When mice were treated with reserpine, which is thought to prevent the intraneuronal storage of dopamine, there was an increase in the striatal concentration of DOPAC which preceded an increase in the concentration of HVA. Since non-cholinergic nerve endings of rat brain contain mitochondria and show monoamine oxidase activity, this result suggests that DOPAC is formed intraneuronally.5. It is concluded that the DOPAC in the striatum represents intraneuronal metabolism of dopamine and that only the HVA which is sensitive to the action of probenecid represents entirely extraneuronal metabolism of this amine. Some of the HVA is not sensitive to the action of probenecid. This suggests that part of the metabolism of dopamine involved both locations.6. A group of drugs which are chemically related to amphetamine were tested for their effects on the concentrations of DOPAC and HVA in the striatum. It is suggested that D-amphetamine, 2-aminotetralin and 1,2,3,4-tetrahydroisoquinoline reduced the intraneuronal metabolism of dopamine whereas adamantanamine did not.

Amantadine↗
PubMed1971

Some observations on the estimation of 3-methoxytyramine in brain tissue.

1. A new method for the estimation of 4-hydroxy-3-methoxyphenylethylamine (3-methoxytyramine) in brain tissue is described. This is based on the formation of a fluorescent derivative by oxidation with potassium ferricyanide in ammonium hydroxide solution.2. The effects of some drugs on the concentration of 3-methoxytyramine in the brain are reported.3. The significance of changes in the striatal concentration of 3-methoxytyramine is discussed.

Amphetamine↗
PubMed1970

Effect of drugs used in psychoses on cerebral dopamine metabolism.

1. Chlorpromazine 15 mg/kg, given daily to cats for 2 weeks, produced a rise in homovanillic acid (HVA) content of the caudate nucleus, whereas the same dose of thioridazine lacked this effect. Of these two drugs, only chlorpromazine causes a high incidence of drug-induced Parkinsonism in man.2. In the mouse, chlorpromazine, thioridazine and haloperidol increased striatal concentrations of HVA and accelerated the disappearance of dopamine (DA) after inhibition of catecholamine synthesis with alpha-methyltyrosine. Low doses of the three compounds increased, whereas high doses reduced, the concentration of DA in the striatum. In their effects on the DA metabolism of the mouse, chlorpromazine and thioridazine had the same potency, but haloperidol was between 10 and 100 times more active than the other two drugs. In producing hypothermia and sedation, the three compounds were equiactive.3. Oxypertine, another drug apt to produce Parkinsonism in man, caused a severe reduction in striatal DA and hypothalamic noradrenaline (NA). Though the clinical signs produced in the mouse were indistinguishable from those seen after the same dose of chlorpromazine, the biochemical changes in the brain were thus quite different.4. Though all the drugs used caused temporary motor disabilities in animals, these bore no resemblance to human Parkinsonism, even when treatment was continued for 7 weeks or more as it was in cats and monkeys. The latter were treated with chlorpromazine 7.5 mg/kg daily, a dose chosen to avoid loss of weight and which may have been too small to produce toxic side-effects. It caused no changes in striatal DA turnover.5. Even at the high dose of 50 mg/kg, phenoxybenzamine did not increase DA turnover in mouse brain, but it sedated the mice as did the tranquillizers.6. Atropine sulphate, 25 mg/kg, reduced the HVA content of mouse striatum and partially antagonized the rise in HVA produced by phenothiazines. The effect was surmountable. Possible modes of action of atropine are discussed.7. At present we know of two types of biochemical changes which may occur in the brain of animals after treatment with drugs apt to cause Parkinsonism in man: a loss of cerebral catecholamines, as seen after reserpine or oxypertine, or an increase in turnover of DA as after phenothiazines and butyrophenones.

Animals↗
PubMed1970

Acid metabolites of monoamines in avian brain; effects of probenecid and reserpine.

1. The concentration of the dopamine (DA) metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the anterior part of the nucleus basalis of pigeon brain was found to be 0.17 +/- 0.01 mug/g, which is about one-fifth of the concentration of homovanillic acid (HVA) in this region. In the chicken, the concentration of HVA in the (entire) nucleus basalis was 0.06 +/- 0.006 mug/g, lower than in any other species examined, and giving a ratio of DA to HVA of about 50. The concentration of DOPAC in the 8 day old chick was 0.053 +/- 0.002 mug/g.2. Probenecid, 200 mg/kg intramuscularly, doubled the content of DOPAC in the nucleus basalis of the pigeon and increased the concentration of HVA in both the pigeon and the chicken by a factor of 4 to 5. These findings demonstrate the existence, in avian brain, of an active transport mechanism for the removal of acidic substances and explain the low concentrations of the acids found in bird brain.3. A method is described for the estimation of 5-hydroxytryptamine (5-HT) and 5-hydroxyindolylacetic acid (5-HIAA) in the same tissue sample. Probenecid caused an increase in the 5-HIAA content but produced no change in the 5-HT content of the nucleus basalis of pigeon brain.4. Reserpine caused a fall in the content of acidic DA metabolites in the nucleus basalis of the pigeon. The effect was more pronounced after raising the concentration of these acids with probenecid.5. Treatment of pigeons with pargyline (100 mg/kg 17 hr before decapitation) did not significantly increase the DA content of the nucleus basalis, but it prevented to some extent the loss in DA caused by reserpine.6. Pigeons and chickens were sedated by probenecid. The deepest sedation occurred at about the same time as the greatest increase in the acidic amine metabolites in the brain.7. Intracisternal injection of HVA in the pigeon and intravenous injection of large amounts of HVA, DOPAC, 5-HIAA or 3,4-dimethoxyphenylacetic acid into newly hatched chicks did not produce any sedation or other effects on behaviour. In contrast, injection of sodium gamma-hydroxybutyrate caused paralysis followed by prostration and eye closure.8. Estimation of the concentration of HVA in the brain of the young chick after intravenous injection of the acid (100 mg/kg) showed that the concentration was of the same order of magnitude as it is in animals given probenecid; this suggests that the sedation which follows probenecid is not related to the accumulation of acidic amine metabolites.

Animals↗
PubMed1970

The concentration of catecholamines in the brain of the domestic fowl (Gallus domesticus).

1. The concentrations of adrenaline and noradrenaline in the brains of chickens (Gallus domesticus) have been determined using two different methods of fluorimetric analysis.2. The concentrations of adrenaline, noradrenaline and also dopamine were found to increase with age, as did the relative amount of adrenaline present in the chicken brain.3. It was observed that the differential assay of adrenaline by the trihydroxyindole method often underestimated the amount of adrenaline present.

Age Factors↗
PubMed1969

Glycol metabolites of noradrenaline in brain tissue.

1. A gas chromatographic method using electron capture detection is described for the estimation of those catecholamines and their metabolites which possess one or two free alcoholic hydroxyl groups. It is based on acetylation of phenolic hydroxyl and primary and secondary amino groups in aqueous solution, extraction into a water immiscible solvent and esterification of alcoholic hydroxyl groups with heptafluorobutyric anhydride.2. The method has been successfully applied to the detection and estimation of free 4-hydroxy-3-methoxyphenylethylene glycol (MOPEG) and free 3,4-dihydroxyphenylethylene glycol (DOPEG) in hypothalamic brain tissue.3. Although it was possible to measure noradrenaline and normetanephrine by the same method in pure solution, crude tissue extracts could not be used, despite their suitability for estimating the glycol metabolites.

Animals↗
PubMed1969

The effect of tropolone on the formation of 3,4-dihydroxyphenylacetic acid and 4-hydroxy-3-methoxyphenylacetic acid in the brain of the mouse.

1. The development of a very sensitive and specific fluorimetric assay for 3,4-dihydroxyphenylacetic acid has made it possible to measure how inhibitors of the enzyme catechol-O-methyl transferase affect the relative concentrations of this acid and its O-methylated derivative 4-hydroxy-3-methoxyphenylacetic acid (homovanillic acid) in the brains of mice treated with L-3,4-dihydroxyphenylalanine or probenecid.2. It was found that tropolone and tropolone-4-acetamide reduce the concentration of homovanillic acid in the brains of the treated mice to an extent dependent on the dose.3. The concentration of 3,4-dihydroxyphenylacetic acid in the brain was increased by the administration of tropolone or tropolone-4-acetamide but the dose and response were not simply related to one another.4. The results suggest that, in vivo, the formation of 3,4-dihydroxyphenylacetic acid is not always a simple alternative to the formation of homovanillic acid when the enzyme catechol-O-methyl transferase is inhibited.

Animals↗
PubMed1968

Release by tubocurarine of dopamine and homovanillic acid from the superfused caudate nucleus.

1. The release of dopamine and its metabolite homovanillic acid from the ;superfused' caudate nucleus was studied in the cat. Fluorimetric assay of the two compounds was carried out on 30 min samples of artificial cerebrospinal fluid perfused through the anterior horn of one lateral ventricle.2. When tubocurarine 0.5 or 1 x 10(-4) g/ml. was added to the perfusion fluid, amounts of dopamine of the order of 0.1 ng/min, and very much larger quantities of homovanillic acid (up to 8 ng/min) appeared in the perfusing fluid.3. No release of dopamine was obtained under conditions when tubocurarine failed to produce any clinical signs or when gallamine was substituted for tubocurarine.

Animals↗