Effect of the metabotropic glutamate antagonist MPEP on striatal expression of the Homer family proteins in levodopa-treated hemiparkinsonian rats.

RATIONALE: Striatal glutamatergic hyperactivity through the metabotropic receptors and their intracellular signaling pathways is considered critical in the development of levodopa-induced dyskinesias in Parkinson's disease and in experimental parkinsonism. OBJECTIVE: We investigated whether the administration of the metabotropic glutamate antagonist, MPEP, modifies striatal expression of Homer family proteins which are involved in the intracellular mechanisms mediated by these receptors. MATERIALS AND METHODS: Sprague-Dawley rats were unilaterally lesioned in the nigrostriatal pathway with 6-hydroxydopamine (8 microg) and treated with: levodopa (12 mg/kg, i.p.) plus vehicle (n=10) divided in two daily injections; levodopa plus MPEP (1.5 and 3 mg/kg, i.p.; n=6-13) divided in two daily injections; or saline (n=7) for 10 consecutive days. Axial, limb, and orolingual dyskinesias were evaluated. Striatal expression of tyrosine hydroxylase (TH), Homer 1a, 1b/c, and deltaFosB were measured by Western Blot. RESULTS: Animals treated with levodopa showed an increase of dyskinesia score (p<0.01) that was attenuated by the administration of MPEP (p<0.01). In the ipsilateral side of the lesion, striatal TH expression was decreased (p<0.01). No significant differences in striatal Homer 1a or b/c expression were observed between the groups of treatment. Striatal deltaFosB expression increased in the animals treated with levodopa (p<0.05) being attenuated after MPEP administration (p<0.05). MPEP effect was not paralleled by any modification of striatal Homer proteins expression. CONCLUSIONS: These results suggest that Homer protein family is not causally involved in the development of dyskinetic movements induced by levodopa treatment in this animal model of parkinsonism.

Bilateral subthalamic nucleus lesion reverses L-dopa-induced motor fluctuations and facilitates dyskinetic movements in hemiparkinsonian rats.

Glutamatergic overactivity might be involved in L-dopa-induced motor complications since glutamate antagonists reverse and prevent L-dopa-induced shortening in motor response duration in 6-hydroxydopamine-lesioned (6-OHDA) rats and improve L-dopa-induced dyskinesias in parkinsonian monkeys and in patients with Parkinson's disease (PD). An increase in the subthalamic nucleus (STN) glutamatergic activity is believed to contribute to the pathophysiology of PD. However, the role of STN activity in L-dopa-induced motor complications is not so clear. In this study, the effect of STN lesions on L-dopa-induced motor response complications was investigated in rats with a nigrostriatal pathway lesion induced by 6-OHDA. Animals were injected with 6-OHDA in the medial forebrain bundle and treated with L-dopa or saline for 22 days. On day 16, animals were randomly distributed in groups that underwent surgery in the STN ipsilateral or contralateral to 6-OHDA lesion, or bilateral. Rotational behavior was measured on days 1, 15, and 22. Attenuation of STN activity by contralateral and bilateral, but not ipsilateral, STN lesion reversed the shortening in motor response duration induced by L-dopa. L-dopa administration, but not saline, induced prominent dyskinesias in 6-OHDA-lesioned rats with additional bilateral STN lesions. The results indicate that bilateral lesions of STN potentiate the duration of L-dopa-induced motor response and facilitate chronic L-dopa-induced abnormal involuntary movements in 6-OHDA-lesioned rats. The characteristics of the abnormal involuntary movements observed in these animals are similar to L-dopa-induced dyskinesias in parkinsonian patients and might be useful as an experimental model for the study of L-dopa-induced dyskinesia.