Dopamine replacement therapy with l-DOPA is the most efficacious symptomatic treatment for Parkinson's disease, but its utility is limited by a development of motor fluctuations and abnormal involuntary movements (dyskinesia) in the majority of patients. These complications are attributed to the combined effects of dopaminergic degeneration and non-physiological reinstatement of dopamine transmission by the standard oral medications. There is substantial evidence that this altered state of dopamine transmission causes pathophysiological changes to a variety of non-dopaminergic neurotransmitter systems in the brain. This evidence has prompted an interest in developing drugs that target non-dopaminergic receptors for the purpose of improving l-DOPA-induced dyskinesia and/or motor fluctuations. We here review all the most important categories of non-dopaminergic targets that have been investigated so far, but with a particular focus on modulators of glutamatergic and serotonergic transmission, which continue to inspire significant efforts towards clinical translation. In particular, we discuss both the experimental rationale and the clinical experience thus far gained from studying 5-HT1A and 5-HT1B receptor agonists, NMDA and AMPA receptor antagonists, mGluR5 negative allosteric modulators, mGluR4 positive allosteric modulators, and adenosine A2a receptor antagonists. We also review compounds with complex pharmacological properties that are already used clinically or about to enter an advanced phase of clinical development (amantadine, safinamide, zonisamide, pridopidine, mesdopetam). We conclude with an outlook on possible directions to address unmet needs and improve the chance of successful translation in this therapeutic area.
Keywords: 5-HT1A/B agonist; Adenosine A2a receptors; Basal ganglia; Drug-induced dyskinesias; Glutamate receptors; Metabotropic glutamate receptors.
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