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-HT1A agonists may reduce LID. However, to date, studies with 5-HT1A agonists have suggested a reduction in LID, but with worsening PD disability. Postsynaptic 5-HT2A and 5-HT2C 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-HT1A, presynaptic 5-HT1B/1D receptors and 5-HT2C 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.