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Parkinson's disease--opportunities for novel therapeutics to reduce the problems of levodopa therapy.
Prog Brain Res. 2008; 172:479-94.PB

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.

Authors+Show Affiliations

Movement Disorders Clinic, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada. sfox@uhnresearch.caNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

18772047

Citation

Fox, Susan H., et al. "Parkinson's Disease--opportunities for Novel Therapeutics to Reduce the Problems of Levodopa Therapy." Progress in Brain Research, vol. 172, 2008, pp. 479-94.
Fox SH, Chuang R, Brotchie JM. Parkinson's disease--opportunities for novel therapeutics to reduce the problems of levodopa therapy. Prog Brain Res. 2008;172:479-94.
Fox, S. H., Chuang, R., & Brotchie, J. M. (2008). Parkinson's disease--opportunities for novel therapeutics to reduce the problems of levodopa therapy. Progress in Brain Research, 172, 479-94. https://doi.org/10.1016/S0079-6123(08)00923-0
Fox SH, Chuang R, Brotchie JM. Parkinson's Disease--opportunities for Novel Therapeutics to Reduce the Problems of Levodopa Therapy. Prog Brain Res. 2008;172:479-94. PubMed PMID: 18772047.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Parkinson's disease--opportunities for novel therapeutics to reduce the problems of levodopa therapy. AU - Fox,Susan H, AU - Chuang,Rosalind, AU - Brotchie,Jonathan M, PY - 2008/9/6/pubmed PY - 2009/1/16/medline PY - 2008/9/6/entrez SP - 479 EP - 94 JF - Progress in brain research JO - Prog Brain Res VL - 172 N2 - 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. SN - 1875-7855 UR - https://www.unboundmedicine.com/medline/citation/18772047/Parkinson's_disease__opportunities_for_novel_therapeutics_to_reduce_the_problems_of_levodopa_therapy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0079-6123(08)00923-0 DB - PRIME DP - Unbound Medicine ER -