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Biomedical subjects

G Curzon

Publications and source records attributed to G Curzon.

At least 127 records · Page 7Linked to original sources
PubMed1980

The effect of L-tryptophan on motor activity and its prevention by an extracerebral decarboxylase inhibitor and by 5-HT receptor blockers.

L-Tryptophan at moderately low dosage (20 mg/kg) reduced the activity of rats taken during a dark period (red light) and put into an open field illuminated by bright white light. Activity was not altered when the field was illuminated by red light. Tryptophan did not cause significant hypoactivity in rats pretreated with the 5-hydroxytryptamine (5-HT) receptor antagonists methysergide, cyproheptadine and metergoline. However, tryptophan did not alter brain 5-HT concentration and only increased 5-hydroxyindoleacetic acid (5-HIAA) slightly in rats killed shortly after behavioural observation. A further indication that the behavioural effect of tryptophan was not due to increased brain 5-HT was its prevention by R04-4602 at a dose sufficient to block peripheral but not central L-aromatic amino acid decarboxylase. The results suggest that the above behavioural effect of L-tryptophan is peripherally mediated. A number of potential mechanisms are discussed.

Animals↗
PubMed1980

Metabolism of an oral tryptophan load. I: Effects of dose and pretreatment with tryptophan.

1 The metabolism of three oral doses of L-tryptophan (50, 25 and 10 mg/kg) in healthy young males has been investigated. 2 There was a linear relationship between both peak and area under curve of the total plasma tryptophan concentrations whilst the relationship between these parameters and plasma free tryptophan was hyperbolic. 3 Before the tryptophan load about 85% of plasma tryptophan was bound to albumin. As plasma tryptophan concentrations increased there was a hyperbolic increase in free tryptophan. Scatchard analysis revealed 1.4 binding sites/molecule albumin with a dissociation constant (Kd) of 57.9 microM. Following administration of L-tryptophan (50 mg/kg) twice daily for 7 days there was no alteration in the number of binding sites but the dissociation constant (Kd) had decreased to 30.9 microM. 4 L-Tryptophan (50 mg/kg twice daily for 7 days) markedly increased both basal plasma total and free tryptophan. However following a further load the total tryptophan curve was comparable to that seen after acute administration. The plasma free tryptophan curve was lowered relative to that seen after an acute dose. 5 Increasing the tryptophan dose shortened the plasma half-life and decreased the volume of distribution and the rate of clearance. Longer term tryptophan administration had no significant effect on plasma half-life or volume of distribution but did decrease the rate of plasma clearance. 6 The plasma kynurenine concentration increased with increasing tryptophan dose and basal concentrations increased markedly after longer term tryptophan administration. 7 Tryptophan administration either acutely or chronically produced little change in urinary tryptophan or 5-hydroxyindole acetic acid excretion. Urinary kynurenine and indole acetic acid excretion increased with increasing doses of tryptophan. 8 Data are discussed in relation to the administration of L-tryptophan for the treatment of depression.

Administration, Oral↗
PubMed1980

Metabolism of an oral tryptophan load. II: Effect of pretreatment with the putative tryptophan pyrrolase inhibitors nicotinamide or allopurinol.

1 The effect of seven days administration of either allopurinol (300 mg daily) or nicotinamide (500 mg twice daily) on the metabolism of an oral L-tryptophan load (50 mg/kg) has been investigated. 2 Administration of either drug failed to alter the plasma total or free tryptophan or plasma kynurenine curve. Nor was the urinary excretion of tryptophan, kynurenine, 5-hydroxyindoleacetic acid or indole acetic acid influenced. 3 Allopurinol pretreatment did increase the volume of distribution of tryptophan. 4 These data suggest that allopurinol and nicotinamide are unlikely to be of value as tryptophan pyrrolase inhibitors in vivo and therefore would not increase the therapeutic effect of L-tryptophan when it is given to treat depressive illness.

Administration, Oral↗
PubMed1980

Effects of albumin, amino acids, and clofibrate on the uptake of tryptophan by the rat brain.

The influences of total tryptophan concentration, albumin binding, and amino acid competition on the rate of tryptophan influx into rat brain were compared using a single-pass injection technique with tritiated water as a freely diffusible reference. Omission of 3% bovine albumin froma bolus containing tryptophan in Krebs-Ringer bicarbonate buffer injected into the carotid artery increased non-albumin bound (free) tryptophan concentration threefold but tryptophan uptake by only 35% and 30% into forebrain and hypothalamus, respectively. However, tryptophan uptake from injected rat plasma was more markedly elevated when free tryptophan concentration was raised. Thus, when free tryptophan was doubled, but total tryptophan unchanged, by in vitro addition of clofibrate to a plasma bolus, uptake was increased by 53% and 28% into forebrain and hypothalamus respectively. When clofibrate was injected in vivo so that plasma total tryptophan concentration was decreased by 45% but neither free tryptophan nor competing amino acid concentrations were altered, then uptake from a bolus of the rat's own plasma was unchanged. Addition of competing amino acids at physiological concentrations to tryptophan in Krebs-Ringer buffer significantly reduced tryptophan influx into both brain regions, but did not increase the effect of albumin binding. The results indicate that tryptophan uptake into rat forebrain is substantially influenced by albumin binding and competition from other amino acids, but that hypothalamic uptake is less influenced by these factors.

Amino Acids↗
PubMed1980

Effect of dialysis on plasma and CSF tryptophan and CSF 5-hydroxyindoleacetic acid in advanced renal disease.

Patients with uraemic encephalopathy were previously found to have low total tryptophan (bound plus free), but high free tryptophan concentrations in the plasma and high CSF tryptophan concentrations. The 5-hydroxytryptamine metabolite 5-hydroxyindoleacetic acid was also raised in the CSF. A study of the effect of dialysis treatment on these substances in chronic uraemic patients with and without dialysis dementia is described. After an episode of dialysis the patients without dialysis dementia showed increased plasma total tryptophan and decreased free tryptophan. These changes were associated with a decrease of plasma free fatty acid. The patients with dialysis dementia did not show changes in tryptophan, but plasma free fatty acid rose. CSF concentrations of 5-hydroxyindoleacetic acid fell moderately in both groups of patients on dialysis.

Adult↗
PubMed1979

Monitoring 5-hydroxytryptamine release in the brain of the freely moving unanaesthetized rat using in vivo voltammetry.

The possibility of using in vivo voltammetry to monitor 5-hydroxytryptamine (5-HT) release from brain tissue in freely moving unanaesthetized rats has been examined. A potential (+0.2 to +1.0 V) was applied to a micrographite electrode stereotaxically placed within a specific brain region and current changes following the oxidation of electroactive compounds in the vicinity of the electrode tip were recorded. Administration of p-chloroamphetamine (5 mg/kg) produced a large increase in current in the striatum and this could be prevented by pretreatment with p-chlorophenylalanine (150 mg/kg X 2) to deplete brain 5-HT or Fluoxetine (10 mg/kg) which prevents the uptake of p-chloroamphetamine by 5-HT neurones. Fluoxetine (10 mg/kg) caused a small but long lasting increase in current. Stimulation of the median raphe nucleus produced a marked and rapid rise in current in the hippocampus but a much smaller one in the striatum. This response could also be prevented by 24 h pretreatment with p-chlorophenylalanine (150 mg/kg). Seven days after p-chlorophenylalanine administration raphe stimulation again produced an increase in current. Rats under barbiturate anaesthesia showed no clear increase in current either after p-chloroamphetamine or raphe stimulation, indicating that barbiturates may affect neurotransmitter release. The results suggest that 5-HT release can be monitored in the freely moving unanaesthetized rat using in vivo voltammetry, and that a moderate decrease in brain 5-HT concentration leads to a substantial inhibition of drug or stimulation induced release of 5-HT.

Animals↗
PubMed1979

Accelerated ageing or selective neuronal loss as an important cause of dementia?

Extensive biochemical analysis of whole temporal lobe from cases of dementia and controls suggests that Alzheimer's disease is a primary degenerative nerve-cell disorder and not the result of accelerated ageing. There is selective loss of neocortical cholinergic neurones. Transmitter systems apart from the cholinergic system appears to be affected, but to a lesser extent, and there are no significant changes in the caudate nucleus. The change in cholinergic neurones has been confirmed in biopsy samples.

Aged↗
PubMed1979

Relationships between plasma, CSF and brain tryptophan.

In many circumstances plasma free tryptophan correlated better than plasma total tryptophan with brain tryptophan concentration (immobilization, fasting, acute liver failure, some drugs). Also, using a modified Oldendorf method it was found that changes of plasma tryptophan binding considerably affected brain tryptophan uptake. Usually, changes of plasma tryptophan binding and non-esterified fatty acid concentration were associated. This led either to changes of plasma free and brain tryptophan concentrations (see above) or to "buffering" in which the proportion of plasma tryptophan in the free state changed but not its concentration. The plasma free tryptophan-brain tryptophan relationship was confirmed in rats after portocaval anastomosis or sham operation. In these experiments brain tryptophan changes did not correlate with plasma amino acids competing with tryptophan for transport to the brain. Determinations on plasma, lumbar and ventricular CSF from psychiatric patients suggest that plasma free tryptophan concentration provides an index of CSF tryptophan and 5-hydroxyindoleacetic acid concentrations and hence of 5-hydroxytryptamine turnover in the human central nervous system.

Amino Acids↗
PubMed1979

Tryptophan disposition in psychiatric patients before and after stress.

Non-esterified fatty acid and total and free tryptophan were determined in the plasma of psychiatric patients unselected with respect to psychiatric diagnosis and in the plasma of normal subjects before and after physiological and psychiatric tests. Retarded patients had significantly low total and free tryptophan values which correlated negatively with agitation. Total tryptophan fell significantly after testing in the non-retarded subjects. The only biochemical abnormality significantly associated with a diagnosis of primary depression was the rise of plasma non-esterified fatty acid after testing. Thus, tryptophan abnormalities were associated more with psychiatric rating scores than with diagnoses.

Adult↗
PubMed1979

Backward walking and circling: behavioural responses induced by drug treatments which cause simultaneous release of catecholamines and 5-hydroxytryptamine.

1 The roles of catecholamine and 5-hydroxytryptamine (5-HT) release in mediating backward walking and circling were studied in rats. 2 These behaviours occurred in animals given 15 mg/kg intraperitoneally of (+)-amphetamine (which predominantly releases catecholamines) or either p-chloroamphetamine or fenfluramine (which predominantly release 5-HT). They also occurred when smaller doses of (+)-amphetamine (5 mg/kg) and either p-chloroamphetamine (2--5 mg/kg) or fenfluramine (5 mg/kg) were given together. 3 Characteristic dopamine-dependent behaviours (rearing, licking, gnawing) resulting from (+)-amphetamine injection were greatly reduced by p-chloroamphetamine or fenfluramine. 4 Characteristic 5-HT-dependent behaviours (wet dog shake, hind limb abduction) resulting from injection of either p-chloroamphetamine or fenfluramine were unaffected by (+)-amphetamine. 5 Fragmentary backward walking and circling resulting from levallorphan injection (50 mg/kg s.c.) were decreased by (+)-amphetamine at low dosage. 6 Results in general strengthen previous evidence that backward walking and circling are mediated by simultaneous dopamine and 5-HT release. 7 The possible relevance of the above findings to hallucinogenic activity, amphetamine psychosis, schizophrenia and abnormal movements due to L-DOPA treatment is discussed.

Amphetamines↗