L-DOPA-Induced Motor Impairment and Overexpression of Corticostriatal Synaptic Components Are Improved by the mGluR5 Antagonist MPEP in 6-OHDA-Lesioned Rats

Abstract

Levodopa (L-DOPA) is still the most effective drug for the treatment of Parkinson's disease (PD). However, the long-term therapy often triggers L-DOPA-induced dyskinesia (LID). Metabotropic glutamate receptor type 5 (mGluR5) is abundant in the basal ganglia, and its inhibition is thought to modulate postsynaptic excitatory synaptic transmission and glutamate hyperactivity in PD and LID. In this report, we examined the effects of mGluR5-specific antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) on LID and synaptic components in the PD model rat. We found the selective mGluR5 antagonist MPEP attenuated abnormal involuntary movements, prolonged the duration of rotational response, reversed the decrease of left forepaw adjusting steps, and reduced overexpression of striatal mGluR5 in the LID rats. Moreover, our results showed much thicker postsynaptic densities, narrower synapse cleft, as well as the increased ratio of perforated synapses induced by L-DOPA treatment, while coadministration of L-DOPA and MPEP reversed these postsynaptic effects. Finally, MPEP reduced overexpression of the two postsynaptic proteins (PSD-95 and SAP102) induced by L-DOPA treatment. Hence, these results provide evidence that aberrant neural plasticity at corticostriatal synapses in the striatum is closely correlated with the occurrence of LID, and targeted inhibition of mGluR5 by MPEP alleviates LID in the PD rat model.

Keywords: L-DOPA-induced dyskinesia; MPEP; Parkinson’s disease; mGluR5; postsynaptic densities.

Figure 1.

Effects of MPEP on L-DOPA-induced abnormal movements in 6-OHDA-lesioned rats. (a) Axial AIM scores are shown at time points as indicated. (b) Limb AIM scores are shown. (c) Orolingual AIM scores are shown. (d) Total (axial, limb, and orolingual) AIM scores are shown. (e) Rotational response durations are shown. (f) Forepaw adjusting steps are shown. AIM scores, rotational response durations, and forepaw adjusting steps were recorded at 2, 9, 11, 18, and 21 days after L-DOPA application. Rats were daily treated with L-DOPA alone or with MPEP 30 min before L-DOPA for 3 weeks. Data were obtained from 10 animals for each group and are shown as mean± SEM. *p < .05, **p < .01, ***p < .001 versus L-DOPA-treated group. AIM = abnormal involuntary movement; MPEP = 2-methyl-6-(phenylethynyl)pyridine; L-DOPA = levodopa.

Figure 2.

MPEP reversed the L-DOPA-induced increase in striatal mGluR5 expression and postsynaptic protein (PSD-95 and SAP 102) expression in 6-OHDA-lesioned side. The proteins were analyzed from 6-OHDA-lesioned rats with saline treatment, or L-DOPA treatment, or MPEP treatment, or L-DOPA in combination with MPEP treatment. (a) The expression of mGluR5 in four groups. (b) The expression of PSD-95 in four groups. (c) The expression of SAP102 in four groups. Data are obtained from four animals for each group and are represented as mean ±SEM. Upper panel, representative blots; Lower panel, quantitative analysis. *p < .05 versus control group (6-OHDA-lesioned alone) or versus L-DOPA-treated group.*p < .05 versus the saline group; ^†p < .05 versus the saline group; ^#p < .05, ^##p < .01 versus the L-DOPA-treated group. MPEP = 2-methyl-6-(phenylethynyl)pyridine; mGluR5 = metabotropic glutamate receptor type 5; PSD = postsynaptic density; L-DOPA = levodopa.

Figure 3.

Effect of MPEP on the L-DOPA-induced ultrastructural changes of synapses in the 6-OHDA-lesioned striatum of rat. The black arrows indicate postsynaptic density and the white arrows indicate synaptic vesicles in the presynaptic membrane. The micropictures showed the representative changes in striatal synapses in the rats treated with saline (a), L-DOPA (b), MPEP (c), or MPEP plus L-DOPA (d). Scale bars = 500 nm. (e), (f), and (g) show quantitative changes of the proportion of perforated synapses, postsynaptic density length, and synapse cleft width, respectively. Data were obtained from five animals for each group and are represented as mean ±SEM. **p < .01, ***p < .01 versus the saline group; ^†p < .05, ^†††p < .001 versus the saline group; ^#p < .05, ^##p < .01, ^###p < .001 versus the L-DOPA-treated group. MPEP = 2-methyl-6-(phenylethynyl)pyridine; L-DOPA = levodopa.