Abstract
L-DOPA, the most effective drug to treat motor symptoms of Parkinson's disease, causes abnormal involuntary movements, limiting its use in advanced stages of the disease. An increasing body of evidence points to the serotonin system as a key player in the appearance of L-DOPA-induced dyskinesia (LID). In fact, exogenously administered L-DOPA can be taken up by serotonin neurons, converted to dopamine and released as a false transmitter, contributing to pulsatile stimulation of striatal dopamine receptors. Accordingly, destruction of serotonin fibers or silencing serotonin neurons by serotonin agonists could counteract LID in animal models. Recent clinical work has also shown that serotonin neurons are present in the caudate/putamen of patients grafted with embryonic ventral mesencephalic cells, producing intense serotonin hyperinnervation. These patients experience graft-induced dyskinesia (GID), a type of dyskinesia phenotypically similar to the one induced by L-DOPA but independent from its administration. Interestingly, the 5-HT1A receptor agonist buspirone has been shown to suppress GID in these patients, suggesting that serotonin neurons might be involved in the etiology of GID as for LID. In this paper we will discuss the experimental and clinical evidence supporting the involvement of the serotonin system in both LID and GID.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by loss of dopamine (DA) neurons in the substantia nigra
We believe that the potent inhibitory effect of 5,7-dihydroxytryptamine (5,7DHT) lesion on both development and expression of dyskinesia in 6-OHDA-lesioned rats [8], together with the striking suppression of L-DOPA-induced dyskinesia (LID) induced by low doses of 5-HT1A + 5HT1B receptor agonists both in rats and macaques [18] provided unquestionable evidence supporting an important role of serotonin neurons, at least in animal models of PD
This study suggested that L-DOPA treatment may be able to provoke sprouting of serotonin axon terminals and change their morphology, possibly enhancing the fluctuations in extracellular DA concentration, consistent with findings of de la Fuente-Fernandez and coworkers in their positron emission tomography (PET) imaging study [22, 24]
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by loss of dopamine (DA) neurons in the substantia nigra. Abnormal involuntary movements (AIMs) develop in response to sub-chronic L-DOPA treatment in 6-hydroxydopamine (6-OHDA)-lesioned rats and 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, resembling peak-dose dyskinesia seen in patients [1,2,3,4]. Using these models, a number of alterations have been identified at the level of striatal neurons of dyskinetic subjects, such as abnormal trafficking of DA D1 and N-methylD-aspartate (NMDA) receptors [5, 6], leading to alterations in key striatal signaling pathways.
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