Combined 5-HTIA and 5-HTIB receptor agonists for the treatment of L-DOPA-induced dyskinesia

Appearance of dyskinesia is a common problem of long-term L-DOPA treatment in Parkinson's disease patients and represents a major limitation for the pharmacological management of the motor symptoms in advanced disease stages. We have recently demonstrated that dopamine released from serotonin neurons is responsible for L-DOPA-induced dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats, raising the possibility that blockade of serotonin neuron activity by combination of 5-HTIA and 5-HTIB agonists could reduce L-DOPA-induced dyskinesia. In the present study, we have investigated the efficacy of 5-HTIA and 5-HTIB agonists to counteract L-DOPA-induced dyskinesia in 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-treated macaques, the gold standard model of Parkinson's disease. In addition, we have studied the ability of this treatment to prevent development of L-DOPA-induced dyskinesia in 6-OHDA-lesioned rats. The results demonstrate the existence of a potent synergistic effect between 5-HTIA and 5-HTIB agonists in their ability to dampen L-DOPA-induced dyskinesia in the MPTP-treated macaques. Sub-threshold doses of the drugs, which individually produced no effect, were able to reduce the abnormal involuntary movements by up to 80% when administered in combination, without affecting the anti-parkinsonian properties of L-DOPA. Furthermore, chronic administration of low doses of the 5-HTI agonists in combination was able to prevent development of dyskinesia, and reduce the up-regulation of FosB after daily treatment with L-DOPA in the rat 6-OHDA model. Our results support the importance of a clinical investigation of the effect of 5-HTIA and 5-HTIB agonists, particularly in combination, in dyskinetic L-DOPA-treated Parkinson's disease patients.