Dopamin (3-Hydroxytyramin) im Zentralnervensystem und seine Beziehung zum Parkinson-Syndrom des Menschen

Hornykiewicz, O

doi:10.1055/s-0028-1114024

Cited by 90 publications

(32 citation statements)

References 3 publications

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“…Symptoms of Parkinson’s disease (PD) are caused by loss of striatal dopamine (Hornykiewicz, 1962) and typically treated with l -DOPA (Utley and Carlsson, 1965). Over time, most PD patients develop involuntary movements, known as l -DOPA-induced dyskinesia (LID) (Anden et al, 1970) which impair even rudimentary motor tasks (Ahlskog and Muenter, 2001).…”

Section: Introductionmentioning

confidence: 99%

Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models

Thiele

Chen

et al. 2014

Neurobiology of Disease

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Parkinsonian symptoms arise due to over-activity of the indirect striatal output pathway, and under-activity of the direct striatal output pathway. l-DOPA-induced dyskinesia (LID) is caused when the opposite circuitry problems are established, with the indirect pathway becoming underactive, and the direct pathway becoming over-active. Here, we define synaptic plasticity abnormalities in these pathways associated with parkinsonism, symptomatic benefits of l-DOPA, and LID. We applied spike-timing dependent plasticity protocols to corticostriatal synapses in slices from 6-OHDA-lesioned mouse models of parkinsonism and LID, generated in BAC transgenic mice with eGFP targeting the direct or indirect output pathways, with and without l-DOPA present. In naïve mice, bidirectional synaptic plasticity, i.e. LTP and LTD, was induced, resulting in an EPSP amplitude change of approximately 50% in each direction in both striatal output pathways, as shown previously. In parkinsonism and dyskinesia, both pathways exhibited unidirectional plasticity, irrespective of stimulation paradigm. In parkinsonian animals, the indirect pathway only exhibited LTP (LTP protocol: 143.5 ± 14.6%; LTD protocol 177.7 ± 22.3% of baseline), whereas the direct pathway only showed LTD (LTP protocol: 74.3 ± 4.0% and LTD protocol: 63.3 ± 8.7%). A symptomatic dose of l-DOPA restored bidirectional plasticity on both pathways to levels comparable to naïve animals (Indirect pathway: LTP protocol: 124.4± 22.0% and LTD protocol: 52.1± 18.5% of baseline. Direct pathway: LTP protocol: 140.7 ± 7.3% and LTD protocol: 58.4 ± 6.0% of baseline). In dyskinesia, in the presence of l-DOPA, the indirect pathway exhibited only LTD (LTP protocol: 68.9 ± 21.3% and LTD protocol 52.0 ± 14.2% of baseline), whereas in the direct pathway, only LTP could be induced (LTP protocol: 156.6 ± 13.2% and LTD protocol 166.7 ± 15.8% of baseline). We conclude that normal motor control requires bidirectional plasticity of both striatal outputs, which underlies the symptomatic benefits of l-DOPA. Switching from bidirectional to unidirectional plasticity drives global changes in striatal pathway excitability, and underpins parkinsonism and dyskinesia.

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Section: Introductionmentioning

confidence: 99%

Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models

Thiele

Chen

et al. 2014

Neurobiology of Disease

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“…The existence of lower concentrations of dopamine in the caudate nucleus and substantia nigra in Parkinsonian patients than in a control group (Ehringer and Hornykiewicz, 1960;Hornykiewicz, 1962) has led to the suggestion that a change in the metabolism of this amine is associated with the syndrome. This concept is supported by the finding that the main metabolite of dopamine, homovanillic acid, is also present in reduced concentrations in the brain and in the CSF of these patients (Bernheimer and Homykiewicz, 1964;Bernheimer, Birkmayer, Hornykiewicz, Jellinger, and Seitelberger, 1966;Guldberg, Turner, Hanieh, Ashcroft, Crawford, Perry, and Gillingham, 1967;Johansson and Roos, 1967;Guldbcrg, Ashcroft, Turner, and Hanieh, 1969).…”

mentioning

confidence: 99%

Phenolic acid concentrations in the lumbar cerebrospinal fluid of Parkinsonian patients treated with L-dopa

Pullar

Weddell

Ahmed

et al. 1970

Journal of Neurology, Neurosurgery & Psychiatry

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SUMMARY The acid metabolites of dopamine and 5-hydroxytryptamine were estimated in the lumbar cerebrospinal fluid (CSF) of Parkinsonian patients both before and during treatment with L-dopa,' the amino acid precursor of dopamine. An attempt was made to relate clinical improvement to the biochemical results. The dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, showed increases related to the dose of L-dopa, the increase in homovanillic acid concentration being proportionately greater than that of 3,4-dihydroxyphenylacetic acid. The concentration of the 5-hydroxytryptamine metabolite, 5-hydroxyindol-3-ylacetic acid, was unaltered by the drug. Clinical improvement, which in the early stages was evident particularly in the bradykinesia, was found to occur at doses of L-dopa greater than 1-5 g/day. Effective doses of L-dopa gave rise to concentrations of dopamine metabolites in the CSF which were greater than normal. Possible implications of these findings are discussed.The existence of lower concentrations of dopamine in the caudate nucleus and substantia nigra in Parkinsonian patients than in a control group (Ehringer and Hornykiewicz, 1960; Hornykiewicz, 1962) has led to the suggestion that a change in the metabolism of this amine is associated with the syndrome. This concept is supported by the finding that the main metabolite of dopamine, homovanillic acid, is also present in reduced concentrations in the brain and in the CSF of these patients

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“…Although some of this presumably is converted to noradrenaline, which may have independent actions, there is considerable evidence that dopamine itself is an imp orportant 'action substance' in the brain (reviewed in reference 26). Dopamine is found in high concentrations in the basal ganglia of the brain (2,23,16), and lately we have been investigating the relationship of certain of these ganglia to one another, as reflected in their amine content. Our method has consisted of placing unilateral electrolytic lesions in the ventromedial tegmental area of the brain stem of rhesus monkeys.…”

Section: The Problem Of the Function Of Brain Amiuesmentioning

confidence: 99%

Some Problems in the Biochemistry of Antidepressant Drugs

1966

Canadian Psychiatric Association Journal

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Dopamin (3-Hydroxytyramin) im Zentralnervensystem und seine Beziehung zum Parkinson-Syndrom des Menschen

Cited by 90 publications

References 3 publications

Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models

Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models

Phenolic acid concentrations in the lumbar cerebrospinal fluid of Parkinsonian patients treated with L-dopa

Some Problems in the Biochemistry of Antidepressant Drugs

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