Antidyskinetic effect of A2A and 5HT1A/1B receptor ligands in two animal models of Parkinson's disease

Background: The serotonin 5-HT1A/1B receptor agonist eltoprazine suppressed dyskinetic-like behavior in animal models of Parkinson's disease (PD) but simultaneously reduced levodopa (l-dopa)-induced motility. Moreover, adenosine A2A receptor antagonists, such as preladenant, significantly increased l-dopa efficacy in PD without exacerbating dyskinetic-like behavior. Objectives: We evaluated whether a combination of eltoprazine and preladenant may prevent or suppress l-dopa-induced dyskinesia, without impairing l-dopa's efficacy in relieving motor signs, in 2 PD models: unilateral 6-hydroxydopamine-lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. Methods: Rotational behavior and abnormal involuntary movements, or disability and l-dopa-induced dyskinesia were evaluated in 6-hydroxydopamine-lesioned rats and MPTP-treated monkeys, respectively. Moreover, in the rodent striatum, induction of immediate-early gene zif-268, an index of long-term changes, was correlated with dyskinesia. Results: In 6-hydroxydopamine-lesioned rats, combined administration of l-dopa (4mg/kg) plus eltoprazine (0.6mg/kg) plus preladenant (0.3mg/kg) significantly prevented or reduced dyskinetic-like behavior without impairing motor activity. Zif-268 was increased in the striatum of rats treated with l-dopa and l-dopa plus preladenant compared with vehicle. In contrast, rats treated with eltoprazine (with or without preladenant) had lower zif-268 activation after chronic treatment in both the dyskinetic and l-dopa-non-primed groups. Moreover, acute l-dopa plus eltoprazine plus preladenant prevented worsening of motor performance (adjusting step) and sensorimotor integration deficit. Similar results were obtained in MPTP-treated monkeys, where a combination of preladenant with eltoprazine was found to counteract dyskinesia and maintain the full therapeutic effects of a low dose of l-dopa. Conclusions: Our results suggest a promising nondopaminergic pharmacological strategy for the treatment of dyskinesia in PD