Author: Espa E, Song L, Skovgård K, Fanni S, Cenci MA.
Background: Current models of L-DOPA-induced dyskinesia (LID) are obtained by treating dopamine-depleted animals with L-DOPA. However, patients with LID receive combination therapies that often include dopamine agonists.
Objective: Using 6-hydroxydopamine-lesioned rats as a model, we aimed to establish whether adjunct treatment with the D2/3 agonist ropinirole impacts on patterns of LID-related neuroplasticity and drug responses.
Methods: Different regimens of L-DOPA monotreatment and L-DOPA-ropinirole cotreatment were compared using measures of hypokinesia and dyskinesia. Striatal expression of ∆FosB and angiogenesis markers were studied immunohistochemically. Antidyskinetic effects of different drug categories were investigated in parallel groups of rats receiving either L-DOPA monotreatment or L-DOPA combined with ropinirole.
Results: We defined chronic regimens of L-DOPA monotreatment and L-DOPA-ropinirole cotreatment inducing overall similar abnormal involuntary movement scores. Compared to the monotreatment group, animals receiving the L-DOPA-ropinirole combination exhibited an overall lower striatal expression of ∆FosB with a distinctive compartmental distribution. The expression of angiogenesis markers and blood-brain barrier hyperpermeability was markedly reduced following L-DOPA-ropinirole cotreatment vs L-DOPA monotreatment. Significant group differences were moreover detected upon comparing the response to candidate antidyskinetic drugs. In particular, compounds modulating D1 receptor signaling had a stronger effect in the L-DOPA-only group, whereas both amantadine and the selective NMDA antagonist MK801 produced a markedly larger antidyskinetic effect in L-DOPA-ropinirole cotreated animals.
Conclusions: Cotreatment with ropinirole altered LID-related neuroplasticity and pharmacological response profiles. The impact of adjuvant dopamine agonist treatment should be taken into consideration when investigating LID mechanisms candidate interventions in both clinical and experimental settings.