Biomedical subjects

E Mignot

Publications and source records attributed to E Mignot.

153 records · Page 9Linked to original sources

PubMed1985

Study of dopamine turnover by monitoring the decline of dopamine metabolites in rat CSF after alpha-methyl-p-tyrosine.

CSF was continuously withdrawn from the third ventricle of anesthetized rats. CSF 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid concentrations were determined every 15 min by liquid chromatography coupled with electrochemical detection. Acute tyrosine hydroxylase inhibition [with alpha-methyl-p-tyrosine (alpha-MPT)] induced an exponential decline in levels of DOPAC and HVA in CSF. The decline in DOPAC and HVA concentrations was identical in CSF and forebrain but was much slower in the striatum, suggesting that CSF metabolites of 3,4-dihydroxyphenylethylamine (dopamine) reflect whole forebrain metabolites. The decay in CSF DOPAC and HVA levels after dopamine synthesis inhibition was also used as an in vivo index of forebrain dopamine turnover after various pharmacological treatments. Haloperidol pretreatment accelerated this decay, confirming the increase in brain dopamine turnover induced by neuroleptics. After reserpine pretreatment (15 h before), alpha-MPT produced a very sharp decay in levels of DOPAC and HVA. This result indicates that the residual dopamine that cannot be stored after reserpine treatment is very rapidly renewed and metabolized. Nomifensine strongly diminished the slope of DOPAC and HVA level decreases after alpha-MPT, a result which can be explained either by a slower dopamine turnover or by the involvement of storage dopamine pools. These results exemplify the use of monitoring the decay of dopamine metabolites after alpha-MPT administration in the study of the pharmacological action of drugs on the central nervous system of the rat.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1985

Effects of rat ovariectomy on CSF monoamine metabolite levels and elimination.

Cerebrospinal fluid (CSF) was removed from the third ventricle of anesthetized male, female, and ovariectomized rats. CSF 3,4-dihydroxyphenylethylamine and serotonin metabolite levels [dihydroxyphenylacetic acid, homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA)] were determined on 15-min samples by liquid chromatography coupled with electrochemical detection. Monoamine oxidase inhibition was used for studying metabolite turnover in the CSF. No difference was observed between male, ovariectomized, and sham-operated female rats. However, ventricular CSF HVA and 5-HIAA levels were significantly higher in the ovariectomized than in the sham-operated rats. These differences do not reflect effects of ovariectomy on brain metabolite production but indicate slower metabolite elimination from the CSF.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1984

Pizotifen increases 5-HIAA urinary excretion in male healthy volunteers.

A single dose of 0.5 mg pizotifen or a placebo was administered to 10 healthy male volunteers in a double blind cross-over trial. 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) in hourly urine samples were determined by liquid chromatography with amperometric detection. The 5-HIAA levels were strongly correlated with the HVA levels in control samples (r = 0.95, p less than 0.001). Pizotifen produced a significant increase in the urinary 5-HIAA/HVA ratio over the 3 hours following absorption of the drug (+0.21, +0.18, +0.19, p less than 0.05). The increase demonstrates an interaction between pizotifen and 5-HT metabolism, which may be involved in its antimigraine effect.

Adult↗

PubMed1984

Kinetics of drug-induced changes in dopamine and serotonin metabolite concentrations in the CSF of the rat.

Cerebrospinal fluid (CSF) was removed at a constant flow rate of 1 microliter/min from the third ventricle of anesthetized rats. Every 15 min, CSF dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were determined by direct injection of CSF into a liquid chromatographic system coupled with electrochemical detection. Mean CSF concentrations of DOPAC, HVA, and 5-HIAA were 1.29 microM, 0.88 microM, and 2.00 microM, respectively. In order to determine the turnover rates of dopamine (DA) and serotonin, experiments using monoamine oxidase (MAO) inhibition were performed. Tranylcypromine (20 mg/kg i.p.) induced a sharp exponential decrease of CSF DOPAC, HVA, and 5-HIAA, with respective half-lives of 15.60 min, 16.91 min, and 77.23 min. Their respective turnover rates were 3.74, 2.22, and 1.18 nmol X ml-1 X h-1. m-Hydroxybenzylhydrazine (NSD-1015, 100 mg/kg i.p.) and monofluoromethyl-DOPA (100 mg/kg i.p.), two decarboxylase inhibitors, induced a slow exponential decrease of all three CSF metabolites. alpha-Methyl-p-tyrosine (250 mg/kg i.p.) also induced a slow exponential decrease of DOPAC and HVA. These decreases of CSF DOPAC and HVA induced by DA synthesis inhibitors may reflect the turnover of DA in vivo. Haloperidol (0.5 mg/kg i.p.) considerably enhanced CSF DOPAC and HVA without affecting 5-HIAA, confirming that dopaminergic receptors modulate DA neurotransmission in vivo. Haloperidol administered 1.5 h after NSD-1015 did not increase DOPAC and HVA, in contrast to reserpine (5 mg/kg i.p.) injected under the same conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed1984

Brain amine metabolism is reflected in cerebral ventricular CSF.

The choroid plexuses are suspended within the ventricles and account for approximately 75% of CSF production. The sodium-potassium ATPase operates within the choroidal epithelial cells and moves sodium ions towards the ventricular surface and potassium ions in the direction of the stroma. Water flows into CSF along osmotic gradient produced by sodium pump. The existence of extracellular channels by which brain metabolites could passively diffuse into the ventriculosubarachnoid space suggests an excretory role for CSF. Removal of solutes from the CSF could occur across the choroidal epithelium or arachnoid membrane into the blood. Systematically administered monoamine metabolites do not cross the blood-brain or the blood-CSF barrier. The regional concentrations of amine metabolites in the CSF is in part a reflection of the concentration of catecholamines and indoleamines in the immediately adjacent neuronal parenchyma. In order to illustrate the validity of monoamine metabolite determinations in cerebral ventricular CSF we developed a device which allowed for a continuous third ventricular CSF withdrawal in freely moving (or anesthetized) rats at a constant flow of 1 microliter/min. The elevation of biogenic amine metabolites in CSF by probenecid or their decline by monoamine oxidase inhibition was used to assess the rate of turnover of amines. Pharmacological manipulations (yohimbine, haloperidol, ouabain) resulted in mono-amine metabolite fluctuations in CSF similar to those previously described in brain tissue. Insulin administration caused an abrupt decrease in CSF glucose and elevated dopamine and serotonin metabolites in rats which had no access to food. These studies demonstrate the adaptation of in vivo analysis of CSF in rats but also exemplify the usefulness of monoamine metabolite determination in the CSF as indicators of brain function.

Amines↗

PubMed1983

Probenecid sensitive pathway of elimination of dopamine and serotonin metabolites in CSF of the rat.

CSF was removed at a constant flow rate of 1 microliter/min from the third ventricle of anesthetized rats. Five microliter CSF samples were directly injected every 15 min into a liquid chromatographic system coupled with an amperometric detector. Mean CSF values for free dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) were 1.4, 0.9, and 2.6 X 10(-6)M respectively. High doses of probenecid resulted in a linear increase of acidic metabolite concentrations which gave an index of the fractional turnover rates related to the resorption by the weak organic acid carrier. Accumulation rates were 0.24, 0.87, and 1.58 mumol/l/h for DOPAC, HVA and 5-HIAA respectively. This route of elimination was predominant for 5-HIAA while it represented only a small part of total turnover for DOPAC. A high elimination rate constant for HVA validates the use of control levels of this metabolite as an indication of fractional HVA turnover dependent upon probenecid-sensitive carrier.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1983

Determination of alphamethyldopa, dihydroxyphenylacetic acid and 5-hydroxyindolacetic acid in the cerebrospinal fluid of the rat: kinetic study.

Cerebrospinal fluid (CSF) was removed at a constant flow rate of 1 microliter min-1 from the third ventricle of rats and directly analyzed by liquid chromatography coupled with electrochemical detection. The effect of alphamethyldopa (alpha MD) on CSF alpha MD, dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindolacetic acid (5-HIAA) concentrations was studied for 5 h. alpha MD ethyl ester administration resulted in higher alpha MD levels in CSF as compared with alpha MD administration, suggesting a higher bioavailability of the ethyl ester vs the free acid. A specific inhibition of dopamine metabolism was reflected by a reduction in DOPAC levels while 5-HIAA concentrations were unchanged.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1982

Central administration of yohimbine increases free 3-methoxy-4-hydroxyphenylglycol in the cerebrospinal fluid of the rat.

The effect of the alpha2-antagonist, yohimbine, on cerebrospinal fluid 3-methoxy-4-hydroxyphenylglycol (MHPG), dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindolactic acid (5-HIAA) concentrations was studied in vivo. Cerebrospinal fluid was removed at a constant flow rate of 1 microliters/min from the third ventricle of rats and directly analysed by liquid chromatography coupled with electrochemical detection. An intracerebroventricular injection of yohimbine (100 nmol) dramatically increased MHPG levels. These results suggest a functional stimulation of alpha-2 adrenoceptors modulating noradrenergic neurotransmission in vivo.

3,4-Dihydroxyphenylacetic Acid↗

PubMedDate not supplied

Genetic studies in narcolepsy, a disorder affecting REM sleep.

Narcolepsy is a disabling sleep disorder characterized by excessive daytime sleepiness and abnormal manifestations of rapid eye movement (REM) sleep including cataplexy, sleep paralysis, and hypnagogic hallucinations. It is known to be a complex disorder, with both genetic predisposition and environmental factors playing a role. In humans, susceptibility to narcolepsy is tightly associated with a specific HLA allele, DQB1*0602. In humans and canines, most cases are sporadic. In Doberman pinschers and Labrador retrievers, however, the disease is transmitted as an autosomal recessive gene canarc-1 with full penetrance. This gene is not linked with the dog leukocyte antigen complex, but is tightly linked with a marker with high homology to the human mu-switch immunoglobulin gene. We have isolated several genomic clones encompassing the canarc-1 marker and the variable heavy chain immunoglobulin region in canines. These have been partially sequenced and have been mapped onto specific dog chromosomes by fluorescence in situ hybridization (FISH). Our results indicate that the mu-switch-like marker is not part of the canine immunoglobulin machinery. We are continuing to extend the genomic contig using a newly developed canine BAC library and attempting to identify the corresponding human region of conserved synteny.

Animals↗