Further studies on the possible interaction between dopamine and noradrenaline containing neurons in the brain.
TL;DR: The synthesis of noradrenaline in the mouse was inhibited either by blocking dopamine β-hydroxylase with FLA-63 or tyrosine hydroxylases with H 44/68, taking as evidence for an interaction between DA and NA containing neurons in the brain.
About: This article is published in European Journal of Pharmacology.The article was published on 1970-08-01. It has received 92 citations till now. The article focuses on the topics: Tyrosine hydroxylase & Esterase inhibitor.
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TL;DR: The proposed hypothesis is that the deleterious behavioral effects of decreased DA activity may be counterbalanced by a similar decrease occurring in NE activity, such compensation being most likely to occur under conditions of stress.
Abstract: The proposed hypothesis is directed toward explaining a number of disparate findings in terms of a stress-related interaction between the NE- and DA-containing systems in the brain. The deleterious behavioral effects of decreased DA activity, for example, may be counterbalanced by a similar decrease occurring in NE activity, such compensation being most likely to occur under conditions of stress. This hypothesis may have application to the understanding of neurological and mental disorders such as Parkinson's disease and schizophrenia.
407 citations
TL;DR: The basal importance of dopamine neurones for the locomotor function studied in the present paper is illustrated by the marked inhibition by low doses of apomorphine, and the observations with clonidine suggest a somewhat less striking and perhaps less direct influence of noradrenaline neurones on motor activity.
Abstract: Motor activity during the first 5 min in a motility meter was measured in mice given 0.025-3.2 mg/kg of the dopamine and noradrenaline receptor agonists apomorphine and clonidine, respectively. The accumulation of Dopa, as induced by the inhibitor of aromatic amino acid decarboxylase, NSD 1015, was measured in parallel in two dopamine-rich regions, i.e. the limbic system and the corpus striatum, and in two noradrenaline-rich regions, i.e. the neocortex and the lower brain stem. Low doses (0.025-0.2 mg/kg) of apomorphine reduced locomotion in a dose-dependent manner, while the reduction after higher doses was less pronounced, indicating a biphasic dose-response relationship. Clonidine caused a dose-dependent locomotor depression. When low doses of the two drugs were combined, the inhibitory effect observed was at least additive. When clonidine was combined with a high dose of apomorphine (0.8 mg/kg), it caused a significant inhibition of locomotion in a dose of 0.1-0.2 mg/kg, but not after 0.8 mg/kg, indicating a biphasic dose-response relationship. Either drug given alone reduced Dopa accumulation after inhibition of its decarboxylation, in all regions, but smaller doses of apomorphine had a clearcut effect only in the dopamine-rich regions, whereas the lowest dose of clonidine investigated (0.05 mg/kg) had an inhibitory effect on Dopa formation only in the neocortex. The relationship between the dose of apomorphine and Dopa formation in the neocortex appeared biphasic, the highest dose (3.2 mg/kg) having no significant effect. Further, apomorphine in this dose accelerated the disappearance of noradrenaline after inhibition of synthesis by alpha-methyltyrosine. Reversal of reserpine-induced suppression of motor activity was taken to indicate postsynaptic receptor activation. The threshold dose of apomorphine causing reversal was 0.2 mg/kg. The inhibitory effect of e.g. 0.05 mg/kg on locomotion and on Dopa formation suggests a preferential activation of inhibitory autoregulatory dopamine receptors by low doses of this drug. A similar trend was observed for clonidine. The basal importance of dopamine neurones for the locomotor function studied in the present paper is illustrated by the marked inhibition by low doses of apomorphine. On the other hand, the observations with clonidine suggest a somewhat less striking and perhaps less direct influence of noradrenaline neurones on motor activity. Mice with a low motor activity, as induced e.g. by reserpine or, in another experiment, mice adapted to the motility meter, displayed an increased motor activity after higher doses of apomorphine (from 0.2 and 2 mg/kg, respectively), whereas all doses depressed the initial high motor activity. Probably, high motor activity requires active dopamine neurones, making this behaviour more susceptible to interference with autoregulatory mechanisms, whereas a low basal activity may be more affected by activation of postsynaptic dopamine receptors.
314 citations
01 Jan 1977
TL;DR: Clonidine, 2-(2, 6-dichlorophenylamino)-2-imidazoline was the first antihypertensive agent known to act on the central nervous system and its therapeutic value as an agent for controlling high blood pressure has been well established in recent years.
Abstract: Clonidine, 2-(2, 6-dichlorophenylamino)-2-imidazoline, referred to as St 155, Catapresan, Catapres or Catapressan, was the first antihypertensive agent known to act on the central nervous system. Its therapeutic value as an agent for controlling high blood pressure has been well established in recent years and its clinical use is growing.
201 citations
TL;DR: It is suggested that compounds like (-)-3-PPP may be of potential clinical utility in the treatment of psychotic disorders, whilst lacking the seriously incapacitating motor dysfunctions produced by current neuroleptic therapy.
Abstract: The two enantiomers of the putative centrally acting dopamine (DA) autoreceptor agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine, 3-PPP (Hjorth et al. 1981), were pharmacologically evaluated. An extensive series of biochemical and behavioural experiments unexpectedly revealed that both (+)- and (-)-3-PPP showed clear, but differential, effects on the DA receptors. Thus, (+)-3-PPP is a DA agonist with autoreceptor as well as postsynaptic receptor stimulatory properties. In contrast, although (-)-3-PPP similarly activates DA autoreceptors it acts concomitantly as an antagonist at postsynaptic DA receptors. Moreover, both behavioural and biochemical data on motor activity and DA synthesis and turnover suggest a preferential limbic action for the (-)-enantiomer. These results are discussed in terms of the dual antidopaminergic action of (-)-3-PPP coupled with anatomical differences in the feedback organisation in central (viz, limbic vs striatal) DA systems. It is suggested that compounds like (-)-3-PPP may be of potential clinical utility in the treatment of psychotic disorders, whilst lacking the seriously incapacitating motor dysfunctions produced by current neuroleptic therapy.
193 citations
Cites background from "Further studies on the possible int..."
...(see e.g. Carlsson et al. 1975; Persson and Waldeck 1970), the minor 5-HT and NA activity alterations produced by the 3-PPP enantiomers may well be ascribed to their dopaminergic properties....
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187 citations
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2,061 citations
TL;DR: A method for chemical assay of small amounts of adrenaline and noradrenaline in tissues is described, utilizing the difference in the activation spectra of the fluoro-phores to identify the two amines.
Abstract: Summary.
A method for chemical assay of small amounts of adrenaline and noradrenaline in tissues is described. The catechol amines are extracted with perchloric acid. The extracts are passed through a cation exchange column (Dowex 50) which takes up the catechol amines. Elution of the amines from the column is performed by hydrochloric acid. Estimation of the two amines in the eluates is made fluorimetrically after oxidation and rearrangement in alkali. Differentiation between adrenaline and noradrenaline is performed by utilizing the difference in the activation spectra of the fluoro-phores.
993 citations
TL;DR: Supporting evidence for apomorphine acts on the dopamine receptors whereas amphetamine acts by releasing dopamine is given by further functional, biochemical and histochemical studies.
Abstract: Sm,-Recently, Ernst (1967) has reported that the apomorphine-induced compulsive gnawing in rats is not mediated via the release of catecholamines, since it is not reduced by the catecholamine synthesis inhibitors a-methyl-3,4dihydroxyphenylalanine and a-methyltyrosine. On the other hand, the gnawing seen after treatment with (+)-amphetamine is blocked by these synthesis inhibitors. Since the apomorphine-induced gnawing requires an intact corpus striatum and gnawing can also be produced by the catecholamine precursor dihydroxyphenylalanine, Ernst (1967) suggested that apomorphine acts on the dopamine receptors whereas amphetamine acts by releasing dopamine. In the present paper supporting evidence for this view is given by further functional, biochemical and histochemical studies. The functional influence of apomorphine on dopamine neurotransmission in the corpus striatum was examined after unilateral removal of the corpus striatum of adult hooded rats weighing about 200 g (And& Dahlstrom & others, 1966a). A possible action of apomorphine on the noradrenaline receptors of the spinal cord was tested in acutely spinalized adult hooded rats by evaluating the changes in the flexor reflex evoked by pinching the hind limbs. The effect of apomorphine on the dopamine and noradrenaline levels of the brain and spinal cord was determined biochemically (Bertler, Carlsson & Rosengren, 1958; Carlsson & Waldeck, 1958) and histochemically (Falck, Hillarp & others, 1962; Dahlstrom & Fuxe, 1964; Hamberger, Malmfors & Sachs, 1965). Function. These studies were made mainly on rats which had been pretreated with reserpine (10 mg/kg i.p., 3 hr) plus a-methyltyrosine methylester (H 44/68, 500mg/kg, i.p., 2 hr) after removal of the left corpus striatum by suction. After this treatment all the operated animals turned towards the unoperated side (cf. And6n & others, 1966a). After injection of apomorphine (1-25 mg/kg s.c.) these rats changed their position and turned or rotated towards the operated side. This effect began about 5 min after the injection and was evident for about 45-60 min. If apomorphine was given to operated rats not pretreated with reserpineH 44/68 combination, this action of apomorphine, like the gnawing, seemed to be less pronounced. If haloperidol (5 mg/kg i.p.) was given 15-20 min after apomorphine all the rats turned from the operated towards the unoperated side in about 15 min and the gnawing ceased. (+)-Amphetamine (0.5-25 mg/kg s.c.), like apomorphine, made the rats turn or rotate towards the operated side. In contrast to apomorphine, however, this action of amphetamine was not seen after pretreatment with reserpine plus H 44/68 (cf. Weissman, Koe & Tenen, 1966; Hanson, 1967; Ernst, 1967). Apomorphine (25 mg/kg s.c.), in contrast to (+)-amphetamine (05-25 mg/kg s.c.) and ~-3,4-dihydroxyphenylalanine (50-75 mg/kg i.v. 2 hr after nialamide 50 mg/kg i.p.), did not cause a definite increase of the flexor reflex in spinalized rats. Chemistry. The biochemical results obtained in unoperated adult hooded rats are presented in Table 1. Apomorphine caused a retardation of the depletion in brain dopamine produced by H 44/68. The difference between the dopamine levels in the apomorphine-H 44/68 group and in the H 44/68 group is statistically significant (P < 0.001, Student’s r-test). This action of apomorphine on the brain dopamine was blocked by haloperidol. The disappearance of noradrenaline from the brain and the spinal cord after H 44/68 did not seem to be influenced by apomorphine. (+)-Amphetamine did not cause any significant retardation of the dopamine and noradrenaline loss after H 44/68.
894 citations
Journal Article•
TL;DR: Preliminary studies of the pharmacologic consequences of blockade of norepinephrine synthesis indicate impairment of motor activity and mild sedation in cats and guinea pigs and a reduction of the tyramine and nore Pinephrine pressor responses in guinea pig and rats.
Abstract: Repeated administration of the tyrosine hydroxylase inhibitor, α-methyl-tyrosine to guinea pigs decreased catecholamine levels in brain stem, caudate nucleus, heart and spleen to undetectable levels. Serotonin was unaffected. That the catecholamine decrease was a consequence of inhibition of tyrosine hydroxylase was shown by the following: tissue concentrations of norepinephrine failed to rise following monoamine oxidase inhibition and decarboxylase inhibitors failed to block the α-methyl-tyrosine effect; the conversion of tyrosine-C14 to norepinephrine was inhibited whereas that from dopa-H3 was not; and there was a normal uptake of exogenous norepinephrine by heart and spleen in animals pretreated with α-methyl-tyrosine. Preliminary studies of the pharmacologic consequences of blockade of norepinephrine synthesis indicate impairment of motor activity and mild sedation in cats and guinea pigs and a reduction of the tyramine and norepinephrine pressor responses in guinea pigs and rats.
833 citations
TL;DR: A fluorimetric method for the determination of dopamine using differences in fluorescence characteristics at pH about 5.3, microquantities of dopainine can be determined in the presence of at least equal amounts of adrenaline or noradrenaline.
Abstract: Summary.
A fluorimetric method for the determination of dopamine is described. The principle is similar to that employed in the tri-hydroxyindole method for estimating adrenaline and noradrenaline. Utilizing differences in fluorescence characteristics at pH about 5.3, microquantities of dopainine can be determined in the presence of at least equal amounts of adrenaline or noradrenaline.
618 citations