Disappearance Of Dopamine Research Articles

Possible mechanism of the hypotensive action of 2,6-dichlorobenzylidene aminoguanidine: Evidence for central noradrenaline receptor stimulation

The effects of 2,6-dichlorobenzylidene aminoguanidine acetate (DCBAG, Wy 8678, Wyeth Laboratories) have been studied on central monoamine neurons of rats in chemical and physiological experiments. Catecholamine (CA) and 5-hydroxytryptamine (5-HT) turnover was studied by the use of the tyrosine hydroxylase inhibitor, α-methyltyrosine methylester (H 44/68) and the tryptophane hydroxylase inhibitor, α-propyldopacetamide (H 22/54). The degree of CA and 5-HT depletion was studied biochemically and histochemically. Arterial pressure, heart and respiration rate were studied in rats anaesthetized with halothane, and the flexor hindlimb reflex was tested in acutely spinalized rats. Biochemically and histochemically, a dose dependent reduction of H 44/68-induced noradrenaline (NA) depletion was found both in the cerebral cortex and in the hypothalamus suggesting a reduction of NA turnover by DCBAG in doses of 0.1–10 mg/kg. The H 44/68-induced disappearance of dopamine (DA) and the H 22/54-induced disappearance of 5-HT was not changed by DCBAG, 1 mg/kg, but a significant reduction was found after 10 mg/kg. These results suggest a decrease of DA and 5-HT turnover with higher doses. The flexor hindlimb reflex, which is dependent on NA receptor activity, was increased by DCBAG (1–20 mg/kg) in spite of previous reserpine and H 44/68 treatment. It is therefore suggested that the decrease in NA turnover observed could be due to a NA receptor stimulating effect of DCBAG, eliciting a feedback to reduce NA release and turnover. DCBAG (5–500 μg/g) produced a dose-dependent reduction in arterial pressure and heart rate; higher doses also reduced respiratory rate. The CA receptor blocking agent chlorpromazine (5 mg/kg), but not the DA receptor blocking agent spiroperidol (1 mg/kg), blocked the effects of DCBAG on arterial pressure and heart rate. These findings suggest that DCBAG lowers arterial pressure and heart rate by its NA receptor stimulating action. These results give further evidence for the existence of a central NA vasodepressor mechanism.

Effect of prostaglandin E 2 on central and peripheral catecholamine neurons

Effects of prostaglandin E 2 (PGE 2) on catecholamine (CA) release from CA neurons have been studied in two models; influence on field stimulation-induced overflow of tritium from isolated tissues pre-incubated with 3H-CA; influence on dopamine (DA) disappearance in the neostriatum induced by tyrosine hydroxylase inhibition utilizing histochemical fluorescence analysis of catecholamines. In vitro PGE 2 (3 × 10 −6 M) caused a small but probably significant reduction of the field stimulation-induced tritium overflow from central noradrenaline (NA) and central DA nerve terminals and a significant reduction of the stimulation-induced overflow from peripheral NA nerve terminals. In the in vivo experiments PGE 2 in μg amounts was dissolved in Krebs-Ringer bicarbonate buffer and infused into the left neostriatum, whereas buffer alone was infused into the right neostriatum. Infusion of 9–18 μg of PGE 2 reduced the disappearance of DA fluorescence after treatment with the tyrosine hydroxylase inhibitor α-methyl-tyrosine methylester ( H 44 68 ) under resting conditions, but could not counteract the increase in H 44 68 - induced DA disappearance caused by electrical stimulation of the nigro-neostriatal DA pathway. The findings suggest that PGE 2 can modify but not stop the release of DA and NA from central CA nerve terminals and indicate that prostaglandins might act as modulators of central CA neurotransmission.

Increase in brain dopamine after axotomy or treatment with gammahydroxybutyric acid due to elimination of the nerve impulse flow.

Both a unilateral, frontal section of the brain at the level of the caudal hypothalamus (hemisection) and systemic treatment with gammahydroxybutyric acid (GHBA, sodium form, 1.5 g/kg i.p.) increased the dopamine (DA) in the rat forebrain by about 70% in 1 h. Both procedures also markedly decelerated the α-methyltyrosine-induced DA disappearance. The brain noradrenaline was significantly lowered after the hemisection, but was not influenced by the treatment with GHBA given either alone or in combination with α-methyltyrosine.

Effects of spreading depression on the turnover of cerebral dopamine

Unilateral spreading depression (SD), induced in the rat by KCl, causes an increase in the homovanillic acid content of the ipsilateral, but not of the contralateral, cerebral hemisphere without concomitant changes of the dopamine (DA) and 5-hydroxyindoleacetic acid levels. The α-methyl-p-tyrosine-induced disappearance of cerebral DA is accelerated on the side of SD. It is concluded that persistent depolarization of striatal and/or cortical neurones leads to an enhanced DA turnover which is possibly due to disinhibition of the nigro-striatal dopaminergic pathway.

Interaction of atropine-like drugs with dopamine-containing neurones in rat brain.

1. A variety of atropine-like drugs effective in the treatment of drug-induced extrapyramidal syndromes have been investigated with regard to their interaction with dopamine-containing neurones in rat brain.2. Under some conditions benztropine, trihexyphenidyl, atropine and ethopropazine significantly antagonized the chlorpromazine-induced increase in subcortical concentrations of homovanillic acid.3. Most of the atropine-like drugs investigated also decreased the turnover of dopamine in the subcortex as measured by following the disappearance of dopamine after administration of alpha-methyl-p-tyrosine.4. These findings are suggestive that an imbalance between a dopaminergic and cholinergic system might be closely linked to the pathogenesis of extra-pyramidal movement disorders.

Chlorpromazine-cocaine antagonism: Its relation to changes of dopamine metabolism in the brain

Cocaine retarded the disappearance of dopamine from the caudate nuclei of mice after inhibition of catecholamine synthesis by α-methyltyrosine. Administration of cocaine and chlorpromazine together enhanced the decrease of the dopamine concentration in the striatum of mice given α-methyltyrosine. Cocaine augmented the increase in homovanillic acid concentration of the caudate nuclei of rats induced by chlorpromazine. In cocaine-treated mice the increased formation of dopamine elicited by chlorpromazine was less pronounced, as measured after a single i.v. injection of 14C-tyrosine. The results may be explained by inhibition of the reuptake of dopamine by cocaine.

Dynamic characteristic of the 'functional compartment' of dopamine in dopaminergic terminals of the rat striatum.

AbstractRats were injected with α‐methyl‐p‐tyrosine and the disappearance of dopamine in the striatum was examined as a function of time. Two main phases of dopamine decline were detected which probably correspond to the amine utilization in a ‘functional’ and a ‘main storage compartment’ in dopaminergic terminals. Similar observations were made when the turnover of dopamine had been previously accelerated by thioproperazine. In control rats the half‐lives of dopamine were about 9 and 120 min in the ‘functional’ and ‘main storage’ compartments respectively. The rate of dopamine synthesis was estimated to be not less than 13‐2 μg/g/h and the rate of dopamine utilization in the ‘functional compartment’ was calculated to be about four times that of the ‘main storage compartment'.

Importance of nervous impulse flow for the neuroleptic induced increase in amine turnover in central dopamine neurons

The influence of chlorpromazine (10 mg/kg), haloperidol (10 mg/kg), spiroperidol (1 mg/kg) and pimozide (5 mg/kg) on dopamine (DA) turnover in vivo in the rat neostriatum was studied in the absence and presence of nervous impulse flow, using the tyrosine hydroxylase inhibitor, α-methyl-tyrosine methylester (H44/68) followed by biochemical and histochemical analysis of DA. Nervous impulse flow in the nigro-neostriatal DA neurons was impaired by making an acute electrothermic lesion of the DA bundle at the level of the corpus mammillare, 30 min before injecting the neuroleptic drugs. In the absence of nervous impulse flow, practically no DA depletion was obtained after H44/68 treatment, whereas a clearcut reduction was observed on the intact side. Furthermore, the acceleration of H44/68-induced DA disappearance caused by chlorpromazine, haloperidol, spiroperidol and pimozide on the intact side was not seen on the operated side, suggesting that nervous impulse flow is necessary for the neuroleptics to increase central DA turnover. At least part of this increase in DA turnover is due to a compensatory increase in the activity of DA neurons initiated by the DA receptor blockade caused by the neuroleptic drugs.

Mechanism of the γ-hydroxybutyrate-induced increase in brain dopamine and its relationship to “sleep”

The naturally occurring central nervous system depressant γ-hydroxy-butyrate (GHB) and its lactone precursor, γ-butyrolactone (GBL) cause a marked and selective increase in brain dopamine. Concomitant with the increase in brain dopamine, homovanillic acid, a metabolite of brain dopamine, is decreased. GBL also causes a selective increase in the specific activity of brain dopamine but not of brain norepinephrine when rats are injected with 14C-tyrosine. This is probably the result of a compensatory activation of dopaminergic neurons because of a blockade in dopamine release induced by GHB. When catecholamine biosynthesis is inhibited by administration of α-methyl- p-tyrosine, GBL completely blocks the disappearance of subcortical dopamine but exerts no antagonism on the disappearance of subcortical norepinephrine. These observations are suggestive that GBL increases brain dopamine primarily by selectively blocking the release of this monoamine from dopamine containing neurons. Indirect evidence is also presented which suggests that the central nervous system depressant properties of GHB may be related to this block in the release of brain dopamine.

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.

Accumulation and disappearance of catecholamines formed from tyrosine- 14C in mouse brain; effect of some psychotropic drugs

Tyrosine- 14C was administered to conscious mice by i.v. injection or constant rate i.v. infusion. The time course for the accumulation and disappearance of dopamine and noradrenaline formed in brain from the labelled tyrosine was determined. The accumulation of 14C-catecholamines following the infusion of tyrosine- 14C was taken as an index of the synthesis rate of the amines. Turnover of the catecholamines was estimated from the decline in radioactivity following prelabelling of the brain amine stores by i.v. injection of tyrosine- 14C. The procedures were used to study the effect of promethazine, chlorpromazine, haloperidol and desipramine on brain catecholamine metabolism. Chlorpromazine and haloperidol increased both accumulation and disapperance of dopamine formed from tyrosine- 14C. Haloperidol and promethazine slightly increased the disappearance of noradrenaline- 14C whereas desipramine significantly reduced the accumulation of noradrenaline- 14C. The results are taken as evidence that desipramine selectively acts on noradrenaline neurons in the brain, whereas chlorpromazine and haloperidol primarily affect dopamine neurons where synthesis and turnover of the transmitter is increased. The significance of the results in relation to the clinical use of the drugs is discussed.