5-HT1 receptor agonists for the treatment of L-DOPA-induced dyskinesia: From animal models to clinical investigation

Appearance of dyskinesia represents the most problematic side effect during chronic L-DOPA treatment in parkinsonian patients, with serious consequences for the patient's quality of life. These side effects are generally attributed to dysregulation of dopamine (DA) transmission and maladaptive changes in the basal ganglia motor circuits. To date, the NMDA receptor antagonist amantadine is the only drug used in patients to control dyskinesia, but with limited efficacy and side effects. Recent evidence in animal models of PD have demonstrated that L-DOPA-induced dyskinesia (LID) emerges as a consequence of abnormal release of striatal DA from the serotonin neurons, which causes a pulsatile stimulation of dopamine receptors. Accordingly, removal of serotonin innervation by 5,7-dihydroxytryptamine (5,7-DHT) administration or pharmacological silencing of serotonin neuron activity by 5-HT1A or 5-HT1B receptor agonists have been shown to suppress LID in 6-OHDA-lesioned rats, as well as in MPTP-treated monkeys. Despite encouraging results have been obtained in pre-clinical models, clinical trials using 5-HT1A serotonin receptor agonists as anti-dyskinetic agents have been mostly disappointing. However, our pre-clinical data suggest that simultaneous activation of 5-HT1A and 5-HT1B receptors induced a potent synergistic effect on suppression of dyskinesia. Thus, clinical investigations employing a mixed 5-HT1A/1B receptor agonist have been recently initiated, and positive preliminary results have been reported. In this review, we will discuss the recent experimental and clinical evidence supporting a potential therapeutic application of serotonin 5-HT1 receptor agonists in LID.