Cerebral Dopamine Metabolism Research Articles

Striatal dopamine receptor binding in morbidly obese women before and after gastric bypass surgery and its relationship with insulin sensitivity

Striatal dopamine receptor binding in morbidly obese women before and after gastric bypass surgery and its relationship with insulin sensitivity

The effect of electroconvulsive shock on the cerebral metabolism of dopamine and 5-hydroxytryptamine.

Journal Article The effect of electroconvulsive shock on the cerebral metabolism of dopamine and 5-hydroxytryptamine Get access A J Cooper, A J Cooper Unit for Research in Brain Metabolism, Department of Pharmacology, University of Edinburgh Medical School, Teviot Place, Edinburgh 8, Scotland Search for other works by this author on: Oxford Academic Google Scholar A T B Moir, A T B Moir Unit for Research in Brain Metabolism, Department of Pharmacology, University of Edinburgh Medical School, Teviot Place, Edinburgh 8, Scotland Search for other works by this author on: Oxford Academic Google Scholar H C Guldberg H C Guldberg Unit for Research in Brain Metabolism, Department of Pharmacology, University of Edinburgh Medical School, Teviot Place, Edinburgh 8, Scotland Search for other works by this author on: Oxford Academic Google Scholar Journal of Pharmacy and Pharmacology, Volume 20, Issue 9, September 1968, Pages 729–730, https://doi.org/10.1111/j.2042-7158.1968.tb09846.x Published: 12 April 2011 Article history Received: 26 June 1968 Published: 12 April 2011

1-Methyl-1,2,3,4-tetrahydroisoquinoline protects against rotenone-induced mortality and biochemical changes in rat brain

The effect of single and multiple administration of the neurotoxic pesticide, rotenone, and the potentially neuroprotective compound, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), on the concentration of dopamine and its metabolites (homovanillic acid-HVA, 3,4-dihydroxyphenylacetic acid-DOPAC, and 3-methoxytyramine-3-MT)) in three brain areas was studied by high-performance liquid chromatography (HPLC) with electrochemical detection in Wistar rats. The rate of dopamine catabolism in the striatum along the N-oxidative and O-methylation pathways was assessed by calculation of the ratio of dopamine metabolites to dopamine. In addition, the effect of rotenone on mortality and general behavior of rats was investigated. We have found that the neurotoxic pesticide, rotenone, administered in a single dose (12 mg/kg s.c.) did not produce evident behavioral or biochemical effects. In contrast, repeated administration of rotenone in doses (12–15 mg/kg) causing abnormalities in general behavior, produced considerable mortality and dramatic increases in dopamine metabolism, which may be ascribed to an increase in the oxidative pathway. Interestingly, it depressed the concentration of the extracellular dopamine metabolite, 3-MT. These behavioral and biochemical changes were effectively counteracted by administration of 1MeTIQ before each dose of rotenone. In summary, we demonstrated that multiple systemic rotenone injections are strongly toxic, and induce alterations of cerebral dopamine metabolism, and that 1MeTIQ may be considered as a potential protective agent against environmental factors affecting the function of the dopaminergic system.

6-[18F]Fluoro-L-DOPA by radiofluorodestannylation: a short and simple synthesis of a new labelling precursor

This paper describes a short and simple synthesis of a new fully protected stannylated precursor, namely N-(tert-butoxycarbonyl)-3,4-di(tert-butoxycarbonyloxy)-6-trimethylstannyl-L-phenylalanine ethyl ester, for the preparation of 6-[18F]fluoro-L-DOPA, used routinely in our Positron Emission Tomography program on neurodegenerative diseases as a tracer of the cerebral dopamine metabolism. The chemical pathway described for the total synthesis of our labelling precursor uses a straightforward protection sequence. This 4-step chemical synthesis allows the rapid preparation of several grammes of pure material in good overall yield. Regioselective radiofluorodestannylation using [18F]fluorine ([18F]F2, cyclotron-produced isotope, half-life:110 min) gave pure 6-[18F]fluoro-L-DOPA (8) in good radiochemical yield (26% decay-corrected, based on starting [18F]fluorine recovered from the target) in 45–50 min after the End of Bombardment. The product was found to be >99% chemically, radiochemically and enantiomerically pure. © 1998 John Wiley & Sons, Ltd.

Ca 2+ channel blockade prevents lysergic acid diethylamide-induced changes in dopamine and serotonin metabolism

To investigate the effect of a single and multiple administration of lysergic acid diethylamide (LSD) on cerebral metabolism of dopamine and serotonin, male Wistar rats were treated with low and high doses (0.1 and 2.0 mg/kg i.p.) of LSD and the levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, 3-methoxytyramine, serotonin and 5-hydroxyindoleacetic acid were assayed by HPLC in the nucleus accumbens, striatum and frontal cortex. Some rats received nifedipine, 5 mg/kg i.p., before each injection of LSD to assess the effect of a Ca 2+ channel blockade. High-dose LSD treatment (8×2 mg/kg per day) caused a strong stimulation of dopamine metabolism in the nucleus accumbens and striatum, and serotonin metabolism in the nucleus accumbens: the changes were observed 24 (but not 1 h) after the last dose. The changes induced by the low-dose treatment (8×0.1 mg/kg per day) had a different pattern, suggesting the release of dopamine from vesicles to cytoplasm. Co-administration of nifedipine completely prevented the LSD-induced biochemical changes. The results suggest that Ca 2+ channel blocking agents may prevent development of some behavioral consequences of chronically used LSD.

Measures and pitfalls for successful preparation of “no carrier added” asymmetric 6-[ 18F]fluor- l-dopa from 18F-fluoride ion

6-[ 18F]Fluoro- l-dopa (6FD) has been proposed and used for probing cerebral dopamine metabolism by positron emission tomography. Recently a new method for asymmetric synthesis of 6FD has been reported. This method involves synthesis of 6-[ 18F]fluoro-3,4-dimethoxybenzylbromide which is reacted with (S)-1-Boc-2-tert-butyl-3-methyl-4-imidazolidinone. The resulting alkylated compound is then hydrolyzed with hydriodic acid to produce 6FD. This method has been used to produce 6FD and several critical steps that required attention found, in addition to some modification for successful 6FD production. 6FD is prepared in 6–13% radiochemical yield (decay not corrected) after HPLC purification with a production time of 85 min.

Different effects of harmine on plasma concentrations of L-dopa and on cerebral dopamine metabolism in rabbits and rats.

The effects of short-term intravenous administration of harmine, a monoamine oxidase inhibitor, on the plasma concentrations of L-Dopa and on dopamine levels in the brain striata of rats and rabbits after L-Dopa administration were studied. Harmine affects the L-Dopa plasma concentrations in rabbits but not in rats: in fact in the former species the area under the concentration-time curve observed after administration of L-Dopa alone increased significantly when animals were pretreated with harmine. Dopamine striatal levels increased in concert with plasma L-Dopa concentrations after administration of L-Dopa in rats and rabbits. However pretreatment with harmine resulted in a significant increase of dopamine levels in the brain striata of rabbits only. These results suggest that harmine or one of its metabolites affect the brain dopamine system not merely as a type A monoamine oxidase inhibitor but with a modulatory effect, without a precise indication of site or mode of action of harmine.

Central antidopaminergic properties of 2-bromolisuride, an analogue of the ergot dopamine agonist lisuride

2-Bromolisuride (2-Br-LIS), a derivative of the ergot dopamine (DA) agonist lisuride, was investigated in rodents in comparison with the DA antagonist haloperidol with regard to its influence on DA related behaviour, cerebral DA metabolism and prolactin (PRL) secretion. 2-Br-LIS produced catalepsy in mice (ED 50 3.3 mg/kg i.p.), antagonized apomorphine-induced stereotypies in mice (ED 50 0.4 mg/kg i.p.), antagonized DA agonist-induced stereotypies in rats (0.1–1.56 mg/kg i.p.), inhibited locomotor activity in rats (0.025–6.25 mg/kg i.p.), antagonized the hyperactivity produced by various DA agonists in rats (0.025–6.25 mg/kg i.p.) and inhibited the apomorphine-induced hypothermia in mice (0.05–0.78 mg/kg i.p.). 2-Br-LIS (0.03–10 mg/kg i.p.) stimulated DA biosynthesis and DOPAC formation in the striatum and DA rich limbic system of rats, but had no effect on serotonin turnover. In striatum and limbic forebrain of γ-butyrolactone-pretreated rats 2-Br-LIS reversed the apomorphine-induced inhibition of DOPA accumulation. 2-Br-LIS (0.03 – 3 mg/kg) enhanced PRL secretion in intact male rats. These findings indicate DA antagonistic properties of 2-Br-LIS presumably due to blockade of central pre- and postsynaptic DA receptors being of approximately the same order of potency as haloperidol. 2-Br-LIS is the first ergot compound with definite antidopaminergic properties suggesting its potential usefulness as a neuroleptic.

Cerebral dopamine metabolism and stereotyped behaviour in early-weaned piglets

The behavioural response to apomorphine in cattle, sheep and pigs resembles some aberrant, oral behaviour patterns or vices that can occur as the result of restrictive environmental conditions and suggests that central dopaminergic neuronal systems might be involved. This study of the function of central dopaminergic mechanisms indicates that, in early-weaned piglets showing stereotyped snoutrubbing behaviour, there is a reduction in the metabolism of dopamine in parts of the brain receiving a dopaminergic neuronal input. The change in the metabolism of dopamine appears to be associated with the separation of the piglets from the sow and provides further evidence for biochemical changes in the brain occurring as the result of early-weaning.

Estimation of the turnover of 3-methoxytyramine in the rat striatum by HPLC with electrochemical detection: implications for the sequence in the cerebral metabolism of dopamine.

A highly sensitive method for the determination of 3-methoxytyramine (3-MT) in nervous tissue is described. The method is based on a rapidly performed isolation of 3-MT on small columns of Sephadex G 10, followed by reverse-phase high-performance liquid chromatography in conjunction with a rotating disk electrochemical detector. The detection limit of the assay (0.5-1 pmol/tissue sample) is about 10% of control value for microwave-killed rats. 3-MT as well as dopamine could be quantified in the same chromatographic run. Inhibition of catechol-O-methyl transferase with tropolone resulted in an exponential decline of 3-MT. From this exponential decline a turnover rate for 3-MT of 1.9 nmol/gh/h was calculated. In the same group of rats the turnover rate of homovanillic acid was 9.1 nmol/g/h. From these data it is concluded that in the rat striatum about 80% of homovanillic acid is formed from 3,4-dihydroxyphenylacetic acid and 20% from 3-MT.

A DOUBLE-BLIND TRIAL OF TETRABENAZINE, THIOPROPAZATE, AND PLACEBO IN PATIENTS WITH CHOREA

Nine patients with Huntington's chorea and one with chorea were admitted to a double-blind cross-over trial of tetrabenazine, thiopropazate, and placebo. Each of the three phases of treatment lasted 2 weeks and both the therapeutic and unwanted effects of treatment were recorded. Lumbar cerebrospinal fluid (C.S.F.) was examined for metabolites of dopamine and serotonin at the end of each phase of treatment. Improvement in patients with chorea was assessed by eight physicians after watching films showing the patients before treatment and at the end of each stage of the trial. Thiopropazate (P<0·01) and tetrabenazine (P<0·001) both significantly controlled chorea. The administration of tetrabenazine was accompanied by a pronounced rise (p<0·001) in the concentration of homovanillic acid in C.S.F., suggesting increased cerebral dopamine metabolism. The effect of thiopropazate was much smaller and not statistically significant. It is suggested that tetrabenazine is the drug of first choice for the suppression of chorea in patients with Huntington's chorea.

Interaction in the cerebral metabolism of the biogenic amines. Effect of phenelzine on this interaction.

1. Chronic administration of phenelzine to dogs caused the concentrations of homovanillic acid (HVA) in c.s.f. from both the lateral ventricle and cisterna magna to fall to new low levels at which they were maintained.2. After 10-12 days treatment with phenelzine the caudate nucleus had elevated concentrations of dopamine and 3-methoxytyramine and lowered concentrations of 3,4-dihydroxyphenylacetic acid and HVA.3. Intravenous administration of tryptophan to dogs pretreated with phenelzine caused in c.s.f. an increase in the concentrations of HVA and in the caudate nucleus a decrease in dopamine concentration and an increase in the concentrations of its metabolites, 3-methoxytyramine, 3,4-dihydroxyphenylacetic acid and HVA.4. A model is proposed for the cerebral metabolism of dopamine and some of the points at which tryptophan and its metabolites may interact with dopamine metabolism are discussed.

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.