Parkinson's disease--opportunities for novel therapeutics to reduce the problems of levodopa therapy.
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.
Fox
Susan H
SH
Movement Disorders Clinic, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada. sfox@uhnresearch.ca
Chuang
Rosalind
R
Brotchie
Jonathan M
JM
D000818:Animals; D001479:Basal Ganglia / Q000033:anatomy & histology / Q000378:metabolism / Q000473:pathology; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007980:Levodopa / Q000009:adverse effects / Q000627:therapeutic use; D010300:Parkinson Disease / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D020033:Protein Isoforms / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism
D020033:Protein Isoforms; D011985:Receptors, Serotonin; D012701:Serotonin; D007980:Levodopa; D004298:Dopamine