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Cited by 39Parkinson's Disease Mechanisms and TreatmentsNeurological disorders and treatmentsNeurotransmitter Receptor Influence on Behavior

Parkinson's disease: opportunities for novel therapeutics to reduce the problems of levodopa therapy

FOX, S, CHUANG, R, BROTCHIE, J·2008·Progress in brain research
DOI 10.1016/s0079-6123(08)00923-0
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Abstract

Long-term treatment for Parkinson's disease (PD) with the dopamine-precursor levodopa (l-DOPA) results in the development of motor fluctuations, including involuntary movements, termed l-DOPA-induced dyskinesia (LID). Currently, effective treatments for LID are limited. The neurodegenerative processes underlying PD result in loss of serotonin (5-HT) input from the dorsal raphe nucleus (DRN) to the striatum, but to a lesser extent than loss of dopamine input. l-DOPA may be converted to dopamine in remaining serotonergic neurons and the non-physiological release of dopamine may lead to abnormal dopamine receptor stimulation in the striatopallidal pathways and result in the generation of LID. Suppressing the activity of these 5-HT inputs to the striatum via presynaptic 5-HT(1A) agonists may reduce LID. However, to date, studies with 5-HT(1A) agonists have suggested a reduction in LID, but with worsening PD disability. Postsynaptic 5-HT(2A) and 5-HT(2C) receptors in the striatum may modulate dopamine to reduce LID and the atypical antipsychotic, clozapine is effective at reducing LID without worsening PD. Alternatively, postsynaptic 5-HT(1A), presynaptic 5-HT(1B/1D) receptors and 5-HT(2C) receptors may modulate GABA and glutamate release within other basal ganglia nuclei to reduce LID. Thus, 5-HT ligands can modulate basal ganglia function and hence motor function through several receptor subtypes and locations, with potential therapeutic benefit to the motor complications induced by long-term l-DOPA therapy in PD. Future studies are needed to develop 5-HT selective drugs that can reduce LID without affecting the anti-parkinsonian action of l-DOPA.

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  • Other brain regions are probably also involved in L-DOPA-induced AIMs because AIMs occur via integrative changes in multiple neurotransmitter systems throughout the CNS.

    “However, other brain regions are probably also involved because L-DOPA-induced AIMs occur via integrative changes in multiple neurotransmitter systems throughout the CNS, including those present in the striatum, globus pallidus, thalamus, cortical areas, subthalamic nucleus, and cerebellum (Carta et al., 2008;Fox et al., 2008).”

    From Nicotinic receptor-mediated reduction in l-DOPA-induced dyskinesias may occur via desensitization (2010) · cites this paper as Fox et al., 2008

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Authors
FOX, S., CHUANG, R., & BROTCHIE, J.
Affiliations
University of Toronto (CA)
Corresponding author
FOX, S
ORCID
Venue
Progress in brain research
Publisher
Elsevier
Published
2008
Volume
172
Pages
479-494
ISSN
0079-6123 (ISSN-L)
DOI
10.1016/s0079-6123(08)00923-0
OpenAlex
W1531095018
Cited by
39
References
93
Citations by year
2024: 2 · 2022: 1 · 2020: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 1 · 2014: 2 · 2013: 5 · 2012: 3
FWCI
23.36
Type
book chapter
Language
en
Open access
closed
Locations
  • Progress in brain research (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Neurology › Neurological disorders and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
Parkinson's disease, levodopa-induced dyskinesia, motor fluctuations, serotonin receptors, dorsal raphe nucleus, striatum, 5-HT1A receptor agonist, 5-HT2C receptor, 5-HT2A receptor, clozapine, basal ganglia, dopamine release, antipsychotic drugs, motor complications
MeSH terms
Animals, Basal Ganglia, Clinical Trials as Topic, Disease Models, Animal, Dopamine, Dyskinesia, Drug-Induced, Humans, Levodopa, Parkinson Disease, Receptors, Serotonin, Serotonin, Protein Isoforms

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