Serotonergic neurones are not involved in action of L-dopa in Parkinson's disease

Melamed, Eldad; Hefti, Franz; Liebman, James; Schlosberg, Arthur J.; Wurtman, Richard J.

doi:10.1038/283772a0

Cited by 51 publications

(20 citation statements)

References 25 publications

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“…Also, dopa-induced contraversive circling behavior in rats with unilateral nigrostiiatal lesions, which is apparently mediated by dopamine synthesized from dopa in the lesioned striatum [45], was not reduced in animals with combined raphe-striatal lesions. In addition, we found thac selective destruction of serotonergic terminals in the striatum failed to reduce striatal dopa decarboxylase, indicating that these neurons contribute little to the total decarboxylating capacity of the striatum [34]. These findings suggest that striatal serotonergic terminals do not represent an important locus for dopa decarboxylation in parkinsonism.…”

Section: Serotonergic Neuronsmentioning

confidence: 93%

“…However, we have recently shown [34] that in rats with destruction of striatal dopaminergic neurons, the increases in striatal release of dopamine after dopa administration were not prevented by additional destruction of the raphe-striatal serotonergic pathway. Also, dopa-induced contraversive circling behavior in rats with unilateral nigrostiiatal lesions, which is apparently mediated by dopamine synthesized from dopa in the lesioned striatum [45], was not reduced in animals with combined raphe-striatal lesions.…”

Section: Serotonergic Neuronsmentioning

confidence: 97%

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Nonaminergic striatal neurons convert exogenous l‐dopa to dopamine in parkinsonism

Melamed

Hefti

Wurtman

1980

Annals of Neurology

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148

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In intact striatum, the enzyme dopa decarboxylase is localized predominantly in dopaminergic nerve terminals. In Parkinson disease, loss of dopaminergic neurons is associated with massive depletion of striatal decarboxylase activity. Nevertheless, efficacy of exogenous L-dopa in parkinsonism is generally believed to result from its enzymatic decarboxylation to dopamine in the corpus striatum. It has previously been suggested that, after degeneration of nigrostriatal pathways, decarboxylation of administered L-dopa may occur mainly at such striatal sites as surviving dopaminergic terminals, serotonergic neurons, or capillaries; but currently available data do not favor these hypotheses. Recent experimental studies indicate that a substantial amount of decarboxylase activity is localized in striatal interneurons or efferent neurons that may not normally synthesize monoamines. We propose that after depletion of dopaminergic terminals, these nonaminergic striatal neurons may contain a large fraction of residual dopa decarboxylase activity and may represent an important locus for conversion of administered dopa to functional dopamine in the parkinsonian corpus striatum.

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Section: Serotonergic Neuronsmentioning

confidence: 93%

Section: Serotonergic Neuronsmentioning

confidence: 97%

Nonaminergic striatal neurons convert exogenous l‐dopa to dopamine in parkinsonism

Melamed

Hefti

Wurtman

1980

Annals of Neurology

Self Cite

148

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show abstract

“…These serotonergic nerve terminals may play a role in decarboxylating Ldopa to dopamine in nonstriatal sites although this possibility is not supported by a previous study (Melamed et al, 1980). 3-O-methyldopa levels increased equally in all three areas, consistent with the fact that COMT activity is located in glia rather than neurons and thus would be diffusely distributed (Kaplan et al, 1979).…”

Section: Discussionmentioning

confidence: 65%

An in vivo comparison of the capacity of striatal versus extrastriatal brain regions to form dopamine from exogenously administered L-dopa

Brannan

Prikhojan

Yahr

1996

J. Neural Transmission

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We used the technique of cerebral microdialysis to monitor the metabolism of exogenously administered L-dopa and compared dopamine and dopamine metabolite formation in the striatum (a site containing abundant dopamine nerve terminals and dopa-decarboxylase (DDC) activity) versus the cerebellum and occipital cortex (sites with limited dopaminergic innervation and DDC activity). The concentrations of dopamine and the major dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) increased in each brain region following L-dopa perfusion; however, dopamine formation was 90% less in the occipital cortex as compared to the striatum and 95% less in the cerebellum. DOPAC formation was 57% less in the occipital cortex and 74% less in the cerebellum. HVA formation was 42% less in the occipital cortex and 70% less in the cerebellum. The levels of the L-dopa metabolite 3-O-methyldopa and the serotonin metabolite 5-hydroxyindoleacetic acid (5HIAA) were identical in the striatum, occipital cortex, and cerebellum both before and after L-dopa administration. We conclude that brain areas with marked reductions in dopamine nerve terminals and DDC activity have a diminished capacity to synthesize dopamine and also lack storage mechanisms to protect the newly synthesized dopamine from degradative metabolism. The relevance of these findings to the use of L-dopa in treating Parkinson's disease is discussed.

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“…Enhanced stimulation of striatal NMDA receptors seems to contribute to the development of treatment-associated dyskinesia and upregulation of GABA receptors is observed in the GPm of both experimental animals and human PD patients exhibiting dyskinesia [44,50,51]. In the dopamine-depleted PD brain, levodopa is probably converted to active dopamine at serotonergic terminals, and this may contribute to the occurrence of dyskinesia, as motor fluctuations are believed to reflect uncontrolled dopamine release by serotonergic neurons [51][52][53][54]. Therefore, inhibition of serotonin pathways in the basal ganglia may stabilise intrasynaptic dopamine levels and reduce dyskinesia.…”

Section: Changes In the Parkinson's Disease Brain That Cause Dyskinesmentioning

confidence: 99%

“…It is possible that different forms of dyskinesia are generated by distinct pathophysiological mechanisms within the basal ganglia. For example, altered signalling in the GPl and STN may contribute to chorea, but not dystonia [51][52][53][54].…”

Section: Changes In the Parkinson's Disease Brain That Cause Dyskinesmentioning

confidence: 99%

Levodopa, motor fluctuations and dyskinesia in Parkinson’s disease

Müller¹,

Russ

2006

Expert Opinion on Pharmacotherapy

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Parkinson's disease (PD) is one of the most frequent, chronic, progressive degenerative disorders of the CNS, characterised by altered neurotransmission of dopamine in the basal ganglia. This may result in disturbances of movement, mobility and posture symptoms, all of which cause severe disability in PD patients. There is no cure for PD. Current treatment approaches aim at symptomatic improvement with a balance of the altered neurotransmission, particularly in striatal dopaminergic neurons. Levodopa, the metabolic precursor of active dopamine, is the most effective compound in the drug treatment of PD. However, chronic exposure to levodopa and related dopaminergic agents supports an onset of movement behaviour fluctuations and dyskinesia in the long term. Dyskinesia is unwanted, sometimes excessive and causes abnormal facial, body and limb movements that appear in many PD patients who are often dependent on the overall dosage of dopaminergic substitution. This complication of anti-Parkinsonian drug therapy supports disability and reduces quality of life in PD patients and their caregivers. This review focuses on the major clinical features and knowledge on the aetiology of these treatment-associated, long-term side effects of dopaminergic drug treatment in PD. It also gives an overview of existing and potential future treatment-strategies for the management of these troublesome treatment complications that affect motor behaviour in PD patients.

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Serotonergic neurones are not involved in action of L-dopa in Parkinson's disease

Cited by 51 publications

References 25 publications

Nonaminergic striatal neurons convert exogenous l‐dopa to dopamine in parkinsonism

Nonaminergic striatal neurons convert exogenous l‐dopa to dopamine in parkinsonism

An in vivo comparison of the capacity of striatal versus extrastriatal brain regions to form dopamine from exogenously administered L-dopa

Levodopa, motor fluctuations and dyskinesia in Parkinson’s disease

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