A2A receptor antagonists do not induce dyskinesias in drug-naive or l-dopa sensitized rats

l-Dopa, the precursor to dopamine, is currently the gold standard treatment for Parkinson's disease (PD). However, chronic exposure is associated with l-dopa-induced dyskinesias (LIDs), a serious side effect characterized by involuntary movements. Adenosine A_2A receptor antagonists have been studied as a novel non-dopaminergic PD treatment. Because A_2A receptor antagonists do not act on dopamine receptors, it has been hypothesized that they will not induce dyskinesias characteristic of l-dopa. To test this hypothesis in a rodent model, the A_2A receptor antagonists SCH 412348 (3 mg/kg), vipadenant (10 mg/kg), caffeine (30 mg/kg), or istradefylline (3 mg/kg) were chronically (19–22 days) administered to Sprague Dawley rats, and dyskinetic behaviors were scored across this chronic dosing paradigm. Unlike l-dopa, there was no evidence of dyskinetic activity resulting from any of the four A_2A receptor antagonists tested. When delivered to animals previously sensitized with l-dopa (6 mg/kg), SCH 412348, vipadenant, caffeine or istradefylline treatment produced no dyskinesias. When administered in combination with l-dopa (6 mg/kg), SCH 412348 (3 mg/kg) neither exacerbated nor prevented the induction of LIDs over the course of 19 days of treatment. Collectively, our data indicate that A_2A receptor antagonists are likely to have a reduced dyskinetic liability relative to l-dopa but do not block dyskinesias when coadministered with l-dopa. Clinical studies are required to fully understand the dyskinesia profiles of A_2A receptor antagonists.