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New pharmacological avenues for the treatment of l-DOPA-induced dyskinesias in Parkinson's disease: targeting glutamate and adenosine receptors

Introduction: Parkinson's disease (PD) therapy is still centered on the use of l-3,4-dihydroxyphenylalanine (l-DOPA), which is hampered by numerous side effects, including abnormal involuntary movements known as l-DOPA-induced dyskinesias (LIDs). LIDs are the result of pre- and postsynaptic changes at the corticostriatal level, induced by chronic and pulsatile stimulation of striatal dopaminergic receptors. These changes impact on synaptic plasticity and involve also selected, nondopaminergic receptors expressed by striatal projection neurons. Areas covered: Among nondopaminergic receptors, glutamate receptors – NMDA and mGluR5 subtypes in particular – and adenosine A2A receptors are those most likely involved in LIDs. The aim of the present review is to summarize results of studies undertaken with specific antagonists of these receptors, first conducted in animal models of LIDs, which in selected cases have been translated into clinical trials. Expert opinion: Selected antagonists of glutamate and adenosine receptors have been proposed as anti-dyskinetic agents. Promising results have been obtained in preclinical investigations and in initial clinical trials, but long-term safety, tolerability and efficacy studies in patients are still required. The current development of novel antagonists, including tools able to act on receptor mosaics, may provide innovative tools for LIDs management in the next future.