Dopamine Agonist Cotreatment Alters Neuroplasticity and Pharmacology of Levodopa‐Induced Dyskinesia

Abstract Background Current models of levodopa (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 an 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 with 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 after L ‐dopa‐ropinirole cotreatment compared with L ‐dopa monotreatment. Moreover, significant group differences were detected upon examining 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 and candidate interventions in both clinical and experimental settings. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.