The pathological processes underlying Parkinson's disease (PD) involve more than dopamine cell loss within the midbrain. These non-dopaminergic neurotransmitters include noradrenergic, serotonergic, glutamatergic, and cholinergic systems within cortical, brainstem and basal ganglia regions. Several non-dopaminergic treatments are now in clinical use to treat motor symptoms of PD, or are being evaluated as potential therapies. Agents for symptomatic monotherapy and as adjunct to dopaminergic therapies for motor symptoms include adenosine A2A antagonists and the mixed monoamine-B inhibitor (MAO-BI) and glutamate release agent safinamide. The largest area of potential use for non-dopaminergic drugs is as add-on therapy for motor fluctuations. Thus adenosine A2A antagonists, safinamide, and the antiepileptic agent zonisamide can extend the duration of action of levodopa. To reduce levodopa-induced dyskinesia, drugs that target overactive glutamatergic neurotransmission can be used, and include the non-selective N-methyl D-aspartate antagonist amantadine. More recently, selective metabotropic glutamate receptor (mGluR₅) antagonists are being evaluated in phase II randomized controlled trials. Serotonergic agents acting as 5-HT2A/2C antagonists, such as the atypical antipsychotic clozapine, may also reduce dyskinesia. 5-HT1A agonists theoretically can reduce dyskinesia, but in practice, may also worsen PD motor symptoms, and so clinical applicability has not yet been shown. Noradrenergic α2A antagonism using fipamezole can potentially reduce dyskinesia. Several non-dopaminergic agents have also been investigated to reduce non-levodopa-responsive motor symptoms such as gait and tremor. Thus the cholinesterase inhibitor donepezil showed mild benefit in gait, while the predominantly noradrenergic re-uptake inhibitor methylphenidate had conflicting results in advanced PD subjects. Tremor in PD may respond to muscarinic M4 cholinergic antagonists (anticholinergics), but tolerability is often poor. Alternatives include β-adrenergic antagonists such as propranolol. Other options include 5-HT2A antagonists, and drugs that have mixed binding properties involving serotonin and acetylcholine, such as clozapine and the antidepressant mirtazapine, can be effective in reducing PD tremor. Many other non-dopaminergic agents are in preclinical and phase I/II early stages of study, and the reader is directed to recent reviews. While levodopa remains the most effective agent to treat motor symptoms in PD, the overall approach to using non-dopaminergic drugs in PD is to reduce reliance on levodopa and to target non-levodopa-responsive symptoms.

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