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Jacques Glowinski

Bio: Jacques Glowinski is an academic researcher from National Institutes of Health. The author has contributed to research in topics: Norepinephrine (medication) & Reserpine. The author has an hindex of 19, co-authored 20 publications receiving 8141 citations.

Papers
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Journal ArticleDOI
TL;DR: It is revealed that norepinephrine and dopamine are specifically localized in complex systems of neurons in the brain, a finding which lends support to the hypothesis that both amines may be neurotransmitters in the central nervous system.
Abstract: NOREPINEPHRINE is found in appreciable amounts in mammalian brain tissue. VOGT (1954) showed that this amine was unequally distributed in various regions of the cat brain, the highest concentrations being found in the hypothalamus. Similar findings were reported for other animal species (BERTLER and ROSENGREN, 1959a; MCGEER, MCGEER and WADA, 1963) and man (SANO, GAMO, KAKIMOTO, TANAGUCHI, TAKE~ADA and NISHINUMA, 1959). Dopamine is also present in the brain in comparable amounts to norepinephrine (MONTAGU, 1957 ; CARLSSON, LINDQVIST, MAGNUSSON and WALDECK, 1958) but with a different regional distribution, the highest concentrations being in the corpus striatum of both animals and man (BERTLER and ROSENGREN, 1959a; SANO et al., 1959; EHRINGER and HORNYKIEWICZ, 1960; BERTLER, 1961). The anatomical distribution of these two catecholamines in the brain was confirmed by the use of fluorescent histochemical techniques which allow a precise description of the cellular localization of the amines in brain tissue (CARLSSON, FALK and HILLARP, 1962; DAHLSTROM and FUXE, 1964; FUXE, 1965). These techniques revealed that norepinephrine and dopamine are specifically localized in complex systems of neurons in the brain, a finding which lends support to the hypothesis that both amines may be neurotransmitters in the central nervous system. The metabolism of catecholamines in the rat brain was studied by introducing small amounts of radioactive norepinephrine or dopamine directly into the lateral ventricle (MILHAUD and GLOWINSKI, 1962, 1963; GLOWINSKI, KOPIN and AXELROD, 1965; GLOWINSKI, IVERSEN and AXELROD, 1966). By this approach the blood-brain barrier to catecholamines can be circumvented, penetration of the radioactive catecholamines into the brain being allowed. The disposition of PHInorepinephrine in the whole brain indicates that [3H]norepinephrine introduced into the lateral ventricle of the brain mixes with the endogenous amine and can be used as a tracer to study the biochemical behaviour of norepinephrine in the brain (GLOWINSKI and AXELROD, 1966). PHIDopamine, which is also taken up and retained in the brain, is rapidly metabolized and converted to norepinephrine (GLOWINSKI et a!., 1966). The unequal regional distribution of the endogeneous catecholamines in the brain led us to undertake a study of the disposition of radioactive norepinephrine and dopamine in various brain regions after intraventricular injection. The regional

5,385 citations

Journal ArticleDOI
26 Dec 1964-Nature
TL;DR: A procedure which made it possible to introduce tritiated-noradrenaline of high specific activity into the rat brain by an intraventricular injection is described and it will be shown that imipramine and structurally related antidepressant drugs but not chlorpromazine block the uptake of tritiates in the brain.
Abstract: IMIPRAMINE is one of the most effective drugs for the alleviation of mental depression. There is little information concerning the mechanism of action of this drug at the biochemical level. An impressive body of evidence has been accumulating over the past few years indicating that noradrenaline is involved in behaviour. Although other antidepressant drugs such as monoamine oxidase inhibitors1, and amphetamine2, affect cerebral noradrenaline concentration, imipramine was found to have no measurable effect on the level of the neurohumour in the brain3.It has been shown that imipramine blocks the uptake of noradrenaline in peripheral tissues4 and brain slices5; however, many other drugs including the tran-uillizer chlorpromazine have the same action5,6. Because noradrenaline cannot cross the blood-brain barrier, it was virtually impossible to examine directly the action of imipramine or other drugs on the uptake of noradrenaline by the intact brain. We have recently described a procedure which made it possible to introduce tritiated-noradrenaline of high specific activity into the rat brain by an intraventricular injection. The tritiated-noradrenaline is taken up and retained by nerve endings in the brain and then shows the essentially same biochemical behaviour as the endogenous neurohumour7. This technique enabled us to investigate the effect of imipramine on the uptake of tritiated-noradrenaline by the intact rat brain. It will be shown that imipramine and structurally related antidepressant drugs but not chlorpromazine block the uptake of tritiated-noradrenaline in the brain.

487 citations

Journal ArticleDOI
TL;DR: The development of techniques for the administration of radioactive norepinephrine into the lateral ventricle of the rat brain allows a direct labelling of the brain catecholamines by exposure to radioactive norpinephrine by measuring the rate of decline of specific activity of the amines after the introduction of small amounts of radioactively labelled catechlamines into the endogenous pools.
Abstract: A CONSIDERABLE volume of information is now available on the distribution of norepinephrine and dopamine in mammalian brain (VOGT, 1954; BERTLER and ROSENGREN, 1959). Recent histochemical findings have demonstrated the presence of these amines in specific neurons in various parts of the brain (CARLSSON, FALCK and HILLARP, 1962; DAHLSTROM and FUXE, 1964; FUXE, 1965). There have also been many reports of changes in the storage levels of catecholamines in the brain in response to centrally-acting drugs (BRODIE, SPECTOR and SHORE, 1959 ; CARLSSON, 1964; LAVERTY and SHARMAN, 1965). However, little is known of the dynamic aspects of the metabolism of catecholamines in the brain. The storage levels of norepinephrine and dopamine are not static but reflect dynamic equilibria between the rates of formation and the rates of utilization of the amines. The turnover of catecholamines has been estimated by measuring the rate of decline of specific activity of the amines after the introduction of small amounts of radioactively labelled catecholamines into the endogenous pools. This approach was first used by UDENFRIEND and WYNGAARDEN (1956) to measure the rate of turnover of adrenal medullary catecholamines after the administration of radioactive precursors. Similarly, the rate of turnover of catecholamines in peripheral sympathetic nerves and brain was measured after the administration of labelled DOPA or tyrosine (UDENFRIEND and ZALTZMAN-NIRENBERG, 1963 ; BURACK and DRASK~CZY, 1964). The presence of a specific uptake mechanism for norepinephrine in sympathetic nerves (WHITBY, AXELROD and WEIL-MALHERBE, 1961 ; HERTTING and AXELROD, 1961 ; IVERSEN, 1963) also allows the direct labelling of norepinephrine stores by exposure to radioactive norepinephrine. This method was used to estimate the rate of turnover of norepinephrine in peripheral tissues (MONTANIRI, COSTA, BEAVEN and BRODIE, 1963) but has hitherto not been applicable to brain since peripherally administered catecholamines do not enter the brain (WEIL-MALEERBE, WHITBY and AXELROD, 1961). The development of techniques for the administration of radioactive norepinephrine into the lateral ventricle of the rat brain (MILHAUD and GLOWINSKI, 1963; GLOWINSKI, KOPIN and AXELROD, 1965), however, allows a direct labelling of the brain catecholamines. Previous studies showed (GLOWINSKI et aZ., 1965) that the half-life for the major phase of disappearance of [3H]norepinephrine from the whole brain after intraventricular administration agrees well with other estimates of the half-life for

397 citations

Journal Article
TL;DR: The different actions of amphetamine and reserpine on the metabolism of H3-norepinephrine indicate the presence of more than one storage form of the brain catecholamine.
Abstract: The effects of drugs and metabolic inhibitors on the uptake, release and metabolism of intraventricularly administered H3-norepinephnine in the rat brain are described. Amphetamine, reserpine and guanethidine, but not cocaine, D-lysergic acid diethylamide, mescaline or bretylium, block the uptake or accumulation of H3-norepinephrine in the brain. Monoamine oxidase inhibition produces an elevation of H3-norepinephrine and H3-normetanephrine in the brain. A catechol O-methyl transferase inhibitor, tropolone-4-acetamide, reduces the level of H3-normetanephrine but has no effect on the level of H3-norepinephrine. Amphetamine and reserpine release H3-norepinephrine in a different manner. Amphetamine administration results in an elevation of normetanephrine levels, while reserpine administration causes an elevation of O-methylated deaminated metabolites. Both drugs release a greater proportion of the brain content of H3-norepinephrine when they are administered a long time after the injection of the radioactive catecholamine than after a short time. The different actions of amphetamine and reserpine on the metabolism of H3-norepinephrine indicate the presence of more than one storage form of the brain catecholamine.

322 citations

Journal Article
TL;DR: The effects of reserpine, a monoamine oxidase inhibitor, Catron (pheniprazine), amphetamine and desmethylimipramine (DMI) on the metabolism of dl -H 3 -norepinephrine were examined in cerebellum, medulla oblongata, hypothalamus, striatum, midbrain, hippocampus and cortex of the rat brain.
Abstract: The effects of reserpine, a monoamine oxidase inhibitor, Catron (pheniprazine), amphetamine and desmethylimipramine (DMI) on the metabolism of dl -H 3 -norepinephrine were examined in cerebellum, medulla oblongata, hypothalamus, striatum, midbrain, hippocampus and cortex of the rat brain. Reserpine reduced the accumulation of H 8 -norepinephrine to varying extents in the different brain regions. In reserpine-pretreated animals, there was also an elevation in the levels of H 3 -deaminated metabolites and a fall in H 3 -normetanephrine in all regions. After Catron, there was an increased accumulation of H 3 -norepinephrine in all areas of the brain except in the striatum; deaminated metabolites were severely reduced, while H 3 -normetanephrine levels were strikingly elevated in all areas of the brain, including the striatum. Both amphetamine and DMI reduced the accumulation of H 3 - norepinephrine in the cerebellum, medulla oblongata and hypothalamus, but produced only small changes in other areas. Amphetamine caused a striking elevation in the levels of H 3 -normetanephrine throughout the brain, while DMI produced only small elevations in the medulla oblongata and cortex. O-methylated deaminated metabolites were unaffected by either drug, though catechol deaminated metabolites were reduced, particularly after amphetamine. H 3 -amphetamine was evenly distributed in the brain at a concentration of about 8 µg/g (5 x 10 -3 M) after an intraperitoneal injection of 15 mg/kg. Amphetamine at this concentration almost completely inhibited the enzymatic deamination of H 3 -norepinephrine in vitro. The levels of H 3 -norepinephrine were reduced in the medulla oblongata, cerebellum and hypothalamus after the intraventricular injection of H 3 -dopamine in d - amphetamine- or DMI-pretreated animals. H 3 -dopamine levels in these regions and in the striatum were unaffected or increased after amphetamine or DMI.

305 citations


Cited by
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Journal ArticleDOI
TL;DR: It is revealed that norepinephrine and dopamine are specifically localized in complex systems of neurons in the brain, a finding which lends support to the hypothesis that both amines may be neurotransmitters in the central nervous system.
Abstract: NOREPINEPHRINE is found in appreciable amounts in mammalian brain tissue. VOGT (1954) showed that this amine was unequally distributed in various regions of the cat brain, the highest concentrations being found in the hypothalamus. Similar findings were reported for other animal species (BERTLER and ROSENGREN, 1959a; MCGEER, MCGEER and WADA, 1963) and man (SANO, GAMO, KAKIMOTO, TANAGUCHI, TAKE~ADA and NISHINUMA, 1959). Dopamine is also present in the brain in comparable amounts to norepinephrine (MONTAGU, 1957 ; CARLSSON, LINDQVIST, MAGNUSSON and WALDECK, 1958) but with a different regional distribution, the highest concentrations being in the corpus striatum of both animals and man (BERTLER and ROSENGREN, 1959a; SANO et al., 1959; EHRINGER and HORNYKIEWICZ, 1960; BERTLER, 1961). The anatomical distribution of these two catecholamines in the brain was confirmed by the use of fluorescent histochemical techniques which allow a precise description of the cellular localization of the amines in brain tissue (CARLSSON, FALK and HILLARP, 1962; DAHLSTROM and FUXE, 1964; FUXE, 1965). These techniques revealed that norepinephrine and dopamine are specifically localized in complex systems of neurons in the brain, a finding which lends support to the hypothesis that both amines may be neurotransmitters in the central nervous system. The metabolism of catecholamines in the rat brain was studied by introducing small amounts of radioactive norepinephrine or dopamine directly into the lateral ventricle (MILHAUD and GLOWINSKI, 1962, 1963; GLOWINSKI, KOPIN and AXELROD, 1965; GLOWINSKI, IVERSEN and AXELROD, 1966). By this approach the blood-brain barrier to catecholamines can be circumvented, penetration of the radioactive catecholamines into the brain being allowed. The disposition of PHInorepinephrine in the whole brain indicates that [3H]norepinephrine introduced into the lateral ventricle of the brain mixes with the endogenous amine and can be used as a tracer to study the biochemical behaviour of norepinephrine in the brain (GLOWINSKI and AXELROD, 1966). PHIDopamine, which is also taken up and retained in the brain, is rapidly metabolized and converted to norepinephrine (GLOWINSKI et a!., 1966). The unequal regional distribution of the endogeneous catecholamines in the brain led us to undertake a study of the disposition of radioactive norepinephrine and dopamine in various brain regions after intraventricular injection. The regional

5,385 citations

Journal ArticleDOI
TL;DR: Recovery of behavioural effects correlated with an increase in the remaining levels of DA in the NAS, and there is evidence that remaining DA levels in theNAS are greater at 90 than at 14 days postoperatively.

1,773 citations

Journal ArticleDOI
TL;DR: In this paper, a novel mechanism for regulating dopamine activity in subcortical sites and its possible relevance to schizophrenia is proposed, which is based on the regulation of dopamine release into sub cortical regions occurring via two independent mechanisms: (1) transient or phasic dopamine release caused by dopamine neuron firing, and (2) sustained, "background" tonic release regulated by prefrontal cortical afferents.

1,771 citations

Journal ArticleDOI
TL;DR: Saturability of D-glucose uptake was demonstrated and evidence presented that all of the five hexoses measurably taken up by brain shared a common carrier, two blood-brain barrier carrier systems for amino acids.
Abstract: OILIENDORF, WILLIAM EL Brain uptake of radiolaMed amino acids, nmines, and hexoses after arterial injection. Am. J. Physiol. 2 2 I(6) : 16294639. 1971 .-The loss of a 14C-labeled test substance to brain during a single capillary passage following rapid injection into the rat common carotid artery was measured relative to a simultaneously injected highly diffusible reference, 3HOHW Twenty-eight amino acids, thirteen amines, seven hexoses, and 5 relatively nondiffusible substances were studied. Amino acid uptakes ranged from unmeasurably low to 55%. Essential nutritional amino acid uptake was greater than nonessential. TWO blood-brain barrier (BBB) carrier systems for amino acids were identified. Putative transmitter substances were much less taken up by brain than precursors. Saturability of D-glucose uptake was demonstrated and evidence presented that all of the five hexoses measurably taken up by brain shared a common carrier. Nonmetabolized cycloleucine and 3-O-methylglucose showed saturable uptakes. Amino acid uptake was incompletely stereo-specific whereas glucose uptake was stereospecific. Phlorizin inhibits brain uptake of D-glucose. Relative BBB permeabilities to many of the test substances resemble red-cell permeabilities. Carrier systems for amino acids are independent of the glucose carrier.

1,649 citations

BookDOI
01 Jan 1994
TL;DR: It is shown that the presence of phosphatase inhibitors can have major effects on the levels of phosphorylation and the activities of the kinase extracted from cells, and the combination of okadaic acid and sodium vanadate was most effective in protecting p34cdc2 against cellular phosphatases.
Abstract: 5 The activity of cyclin-dependent protein kinase p34cdc2 is regulated by phosphorylation. In this study, we show that the presence of phosphatase inhibitors can have major effects on the levels of phosphorylation and the activities of the kinase extracted from cells. The combination of okadaic acid and sodium vanadate was most effective in protecting p34cdc2 against cellular phosphatases. In the absence of these inhibitors, p34cdc2 was dephosphorylated with an altered activity, indicating that phosphatase activities remained high during extractions. In contrast to when both inhibitors were used, lower activity of the kinase was found when only sodium vanadate was used, whereas higher activity was found in the presence of okadaic acid. Other conventional phosphatase inhibitors such as NaP, NaRS03 and glycero12-phosphate, were not effective in preventing dephosphorylation from p34cdc2 in whole cell lysates.

1,308 citations