Involvement of non-dopaminergic systems in L-DOPA-induced dyskinsia

Abstract: Parkinson's disease and L-DOPA-induced dyskinesia (LID) does not merely involve the dopamine (DA) system but also include non-dopaminergic systems such as glutamate and serotonin (5-HT). An aberrant glutamate transmission at the corticostriatal synapse, has been linked to LID. Pharmacological agents to glutamate receptors at this synapse, (of which some are already clinically tested), could prevent the aberrant signalling and the consecutive development of LID. In this thesis, a rat model of the disease was used for evaluating and comparing the following substances for their effects on akinesia or dyskinesia as well as LID-associated molecular and morphological alterations: 1) antagonist for L-type calcium channels, 2) antagonist of the NR2B subtype selective NMDA receptor, 3) agonist of the presynaptic mGluR2/3, 4) antagonist of postsynaptic mGluR1 and 5) mGluR5. Animals were treated chronically with a clinical relevant dose of L-DOPA with or without cotreatment with any of the antagonist/agonist. The L-type calcium channel antagonist isradipine, was shown inefficient in reducing LID. But notably, when isradipine was at an earlier time-point (i.e. at the time of DA denervation) it could prevent pathological alteration in morphology of striatal neurons (induced by the DA depletion), and reduce the development of LID. Therefore, isradipine could, in a prophylactic way, reduce the development of dyskinesia. When comparing the different glutamate targets (given after the DA denervation), results showed that the target of mGluR5 was superior to all other receptors/channel, in relieving LID without compromising the therapeutic effect of L-DOPA. Prompted by these results, another mGluR5 antagonist fenobam, that has been clinically tested, was evaluated in both rat and monkey model of PD. A more efficient alleviation of LID was achieved with a maximum effect of 70%. Thereby, fenobam represents the most effective “antiglutamatergic” drug so far tested in experimental models of Parkinson's and acts similarly in rat and primate models of LID. The second half of the thesis evaluates the 5-HT system. In the DA depleted striatum, L-DOPA is primarily taken up and converted to DA, in the residual striatal 5-HT terminals. However, these do not have an autoregulatory machinery for DA release, and causes excessive DA release as a risk factor for dyskinesia. Here, a new mechanism of maladaptive plasticity induced by chronic L-DOPA treatment was revealed. Analysis of rat and monkey models of LID and post-mortem tissue from PD patients consistently showed a positive association between striatal 5-HT fibre density and the severity of LID. This growth-promoting effect was paralleled with a greater stimulus-evoked DA release in dyskinetic animals compared to saline controls. Taken together, a maladaptive plasticity of 5-HT fibres in the striatum, could be seen as a susceptibility factor for the development of LID. Moreover, it could provide a biomarker for LID.