A(2A) receptor antagonists do not induce dyskinesias in drug-naive or L-dopa sensitized rats

作者：Jones N; Bleickardt C; Mullins D; Parker E; Hodgson R^*

来源：Brain Research Bulletin, 2013, 98: 163-169.

DOI：10.1016/j.brainresbull.2013.07.001

• A(2A) receptor antagonist
• L-Dopa
• Rat
• Dyskinesias
• Catalepsy

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 (I 0 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.

• 出版日期2013-9