title: A2A receptor antagonists do not induce dyskinesias in drug-naive or L-dopa sensitized rats.
abstract: 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 A2A receptor antagonists have been studied as a novel non-dopaminergic PD treatment. Because A2A 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 A2A 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 A2A 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 A2A 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 A2A receptor antagonists.
authors.affiliation: Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA.
authors.forename: N
authors.initials: N
authors.lastname: Jones
authors.forename: C
authors.initials: C
authors.lastname: Bleickardt
authors.forename: D
authors.initials: D
authors.lastname: Mullins
authors.forename: E
authors.initials: E
authors.lastname: Parker
authors.forename: R
authors.initials: R
authors.lastname: Hodgson
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000627:therapeutic use*; D018663:Adrenergic Agents / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D018726:Anti-Dyskinesia Agents / Q000627:therapeutic use; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000503:physiopathology*; D006220:Haloperidol / Q000627:therapeutic use; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D018663:Adrenergic Agents; D018726:Anti-Dyskinesia Agents; D000978:Antiparkinson Agents; D007980:Levodopa; D016627:Oxidopamine; D006220:Haloperidol
keywords: A(2A) receptor antagonist; Catalepsy; Dyskinesias; Rat; l-Dopa