Emerging dysfunctions consequent to combined monoaminergic depletions in parkinsonism
Claire DelavilleJonathan ChetritKhaled AbdallahStéphanie MorinLaura CardoitPhilippe De DeurwaerdèreAbdelhamid Benazzouz
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Abstract Not long after the discovery, in the 1950s, of mammalian brain neurons containing the monoamines noradrenaline (NA), dopamine (DA), and serotonin (5-hydroxytryptamine; 5-HT), biochemical methods were established to monitor the level of monoaminergic neurotransmission and to help us understand how this is altered by psychotropic drugs and the physiological state. These biochemical methods included the measurement, in animal brain tissue, of rates of monoamine synthesis, as well as levels of monoamine metabolites and their rate of clearance. At the same time methods were also developed to measure the efflux of monoamine neurotransmitters from nerve terminals in brain tissue in vitro.
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Major depressive disorder (MDD) is a serious illness with far reaching societal and economic ramifications. The monoamine-deficiency hypothesis that depressive symptoms are associated with reductions in monoamine neurotransmission, particularly serotonin and noradrenaline, is supported by both neurochemical findings and the successful treatment of MDD with compounds that enhance monoaminergic neurotransmission. This review focuses on novel compounds in different stages of development for the treatment of MDD that enhance monoaminergic neurotransmission via a number of different mechanisms, including re-uptake inhibition of one or more monoamines, monoamine oxidase inhibitors, the combination of monoamine antagonists with re-uptake inhibitors and monoamine receptor subtype agonists. Compounds that enhance individual monoamines have antidepressant properties and compounds that enhance multiple monoamines appear to have a synergistic antidepressant effect and potentially faster onset of action. The differing mechanisms of action possessed by these novel monoamine-enhancing compounds will offer greater treatment flexibility in the therapeutic management of MDD.
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Major depressive disorder (MDD) is a serious illness with far reaching societal and economic ramifications. The monoamine-deficiency hypothesis that depressive symptoms are associated with reductions in monoamine neurotransmission, particularly serotonin and noradrenaline, is supported by both neurochemical findings and the successful treatment of MDD with compounds that enhance monoaminergic neurotransmission. This review focuses on novel compounds in different stages of development for the treatment of MDD that enhance monoaminergic neurotransmission via a number of different mechanisms, including re-uptake inhibition of one or more monoamines, monoamine oxidase inhibitors, the combination of monoamine antagonists with re-uptake inhibitors and monoamine receptor subtype agonists. Compounds that enhance individual monoamines have antidepressant properties and compounds that enhance multiple monoamines appear to have a synergistic antidepressant effect and potentially faster onset of action. The differing mechanisms of action possessed by these novel monoamine-enhancing compounds will offer greater treatment flexibility in the therapeutic management of MDD.
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Besides the monoaminergic neurons possessing the whole set of the enzymes of monoamine synthesis from the precursor amino acid and the monoamine membrane transporter, the neurons partly expressing monoaminergic phenotype, one of the enzymes of monoamine synthesis and/or monoamine membrane transporter, have been discovered. The monoenzymatic neurons are widely distributed through the brain being even more numerous than monoaminergic neurons suggesting their important functional role. Most numerous monoenzymatic neurons express individual enzymes of dopamine (DA), tyrosine hydroxylase (TH) or aromatic L-amino acid decarboxylase (AADC). TH is enzymatically active in most monoenzymatic neurons converting L-tyrosine to L-DOPA. AADC is enzymatically active in all studied monoenzymatic neurons converting extracellular L-dihydroxyphenylalanine (L-DOPA) or 5-hydroxytryptophan captured from the extracellular space, to DA or serotonin, respectively. Monoenzymatic neurons expressing complementary enzymes of the DA synthetic pathway synthesize this neurotransmitter in cooperation. The cooperative synthesis of monoamines by non-monoaminergic neurons is believed to be a compensatory reaction under the functional insufficiency of monoaminergic neurons. In addition to monoenzymatic neurons, less numerous non-monoaminergic neurons expressing the serotonin membrane transporter but lacking all the enzymes or only rate-limiting enzymes of monoamine synthesis have been discovered. Although the functional significance of these neurons remains uncertain, they most probably represent a temporal store of serotonin captured within the brain either from the intercellular space or the cerebrospinal fluid. Thus, a substantial number of the brain neurons express partly the monoaminergic phenotype, probably, serving to compensate the functional deficiency of monoaminergic neurons.
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Monoamine neurotransmitters are released by specialized neurons that regulate behavioral and cognitive functions. Although localization of monoaminergic neurons in the brain is well known, the distribution, concentration, and kinetics of monoamines remain unclear. We used mass spectrometry imaging (MSI) for simultaneous and quantitative imaging of endogenous monoamines to generate a murine brain atlas of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) levels. We observed several nuclei rich in both 5-HT and a catecholamine (DA or NE). Additionally, we analyzed de novo monoamine synthesis or fluctuations in those nuclei. We propose that MSI is a useful tool to gain deeper understanding of associations among the localization, levels, and turnover of monoamines in different brain areas and their role in inducing behavioral changes.
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Monoaminergic systems are important modulators of the responses to stress and stress may influence feeding behavior, and the involvement of monoamines in the control of food intake is well to recognize and other functions.
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Event Abstract Back to Event Specific and regionally restricted correlations between monoamine tissue content in cerebral structures involved in cognition. Philippe De Deurwaerdère1, 2*, Aurélie FITOUSSI1, 3, Matéo Laqui1, 3 and Françoise Dellu-Hagedorn1, 3 1 University of Bordeaux 2, Life Sciences, France 2 IMN UMR CNRS 5293, France 3 INCIA UMR CNRS 5287, France The widely spread nature of the dopamine (DA), noradrenalin (NA) and serotonin (5-HT) monoaminergic systems is the main difficulty to foresee their functions and their interactions. We sought to undertake the functional relationships between brain areas within a particular monoamine system network and between distinct monoaminergic systems in various brain areas involved in decision-making, through a global correlational approach of the monoamine tissue content. Bilateral punches of twenty brain regions were taken on a cryostat from each frozen Sprague-Dawley rat brains (n=35). NA, DA and 5-HT tissue contents were measured using a sensitive HPLC/electrochemistry system. Significant correlations were searched for between the monoamine content of brain regions. NA and 5-HT were present in all selected regions at concentrations approximately ranging from 0.07 to 1 ng/mg. DA tissue content, less homogeneous, was higher in dorsomedial striatum (8.6 ng/mg) compared to extrastriatal tissues (<0.5 ng/mg). We found some significant correlations between paired regions within a particular monoamine system (22/190 possible correlations for 5-HT; 16/190 for NA and 12/152 for DA). Correlations were exclusively positive for intracortical relationships. Negative correlations emerged from few cortico-subcortical and subcortical associations (4/6 and 3/9 for DA or 5-HT, respectively). We did not find any correlation between some adjacent brain regions for any monoamine (prelimbic/infralimbic cortex; core/shell accumbens; basolateral/central amygdala). When looking at the correlations between monoamines tissue content within brain areas, we found a higher degree of significant associations. This approach of monoamine function reveals intriguing anatomical correlations that corroborate and extend functional relationships described in the literature of decision-making. These patterns could sustain large inter-individual differences in behavior and adaptability. Keywords: monoamines, Correlation, HPLC, tissue content, Serotonin, Dopamine, noradrenaline, decision-making, Cognition, rat Conference: 4th Conference of the Mediterrarnean Neuroscience Society, Istanbul, Türkiye, 30 Sep - 3 Oct, 2012. Presentation Type: Poster Presentation Topic: Abstracts Citation: De Deurwaerdère P, FITOUSSI A, Laqui M and Dellu-Hagedorn F (2013). Specific and regionally restricted correlations between monoamine tissue content in cerebral structures involved in cognition.. Conference Abstract: 4th Conference of the Mediterrarnean Neuroscience Society. doi: 10.3389/conf.fnhum.2013.210.00020 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 07 Feb 2013; Published Online: 11 Apr 2013. * Correspondence: Prof. Philippe De Deurwaerdère, University of Bordeaux 2, Life Sciences, Bordeaux, 33076, France, deurwaer@u-bordeaux.fr Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Philippe De Deurwaerdère Aurélie FITOUSSI Matéo Laqui Françoise Dellu-Hagedorn Google Philippe De Deurwaerdère Aurélie FITOUSSI Matéo Laqui Françoise Dellu-Hagedorn Google Scholar Philippe De Deurwaerdère Aurélie FITOUSSI Matéo Laqui Françoise Dellu-Hagedorn PubMed Philippe De Deurwaerdère Aurélie FITOUSSI Matéo Laqui Françoise Dellu-Hagedorn Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.
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