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Parkinson ’ s disease (PD) is the second most common neurodegenerative disease after Alzheimer ’ s disease. PD patients exhibit a classic spectrum of motor symptoms, arising when dopamine neurons in the substantia nigra pars compacta are reduced by 60%. The dopamine precursor L-DOPA represents the most effective therapy for improving PD motor dysfunctions, thus far available. Unfortunately, long-term treatment with L-DOPA is associated with the development of severe side effects, resulting in abnormal involuntary movements termed levodopa-induced dyskinesia (LID). Amantadine is the only drug currently approved for the treatment of LID indicating that LID management is still an unmet need in PD and encouraging the search for novel anti-dyskinetic drugs or the assessment of combined therapies with different molecular targets. This review provides an overview of the main preclinical models used to study LID and of the latest preclinical evidence on experimental and clinically available pharmacological approaches targeting non-dopaminergic systems. LIDs are supported by complex molecular and neurobiological mechanisms that are still being studied today. This complexity suggests the need of developing personalized pharmacological approach to obtain an effective amelioration of LID condition and improve the quality of life of PD patients.

Dyskinesia and Parkinson’s disease: animal model, drug targets, and agents in preclinical testing