The appearance of dyskinesia presents new challenges as a symptom of long-term Parkinson’s therapy with levodopa. Our recent studies have identified the serotonin system as a possible target for antidyskinetic therapy. Serotonin neurons can convert the exogenously administered levodopa to dopamine and mediate its release, but serotonin neurons release dopamine in an excessive manner. Accordingly, drugs able to reduce the activity of the serotonin neurons have been shown to suppress dyskinesia.
In this project we will further explore the serotonin neurons as a target to address levodopa-induced dyskinesia. In particular, we will explore whether increase of the serotonergic tone by the administration of the serotonin precursor 5-hydroxytryptophan can counteract the appearance of dyskinesia. We will investigate whether 5-hydroxytryptophan may increase the antidyskinetic efficacy of selective 5-HT1 agonists, such as eltoprazine, a drug currently under clinical investigation to treat dyskinesia.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The appearance of dyskinesia has a major impact on the patient´s quality of life, and to date no drug is known to provide a satisfactory control of dyskinesia. There is therefore a high need for developing new therapeutic strategies to control this side effect of levodopa medication. The identification of the serotonin neurons as major determinants in the appearance of levodopa-induced dyskinesia made them a promising therapeutic target. The optimization of this treatment approach may lead to significant improvement in the management of dyskinesia.
This study is expected to provide a better understanding of the role of serotonin neurons in the appearance and treatment of levodopa-induced dyskinesia, with important clinical implications. According to our preliminary results, administration of the serotonin precursor 5-hydroxytryptophan should provide a significant suppression of dyskinesia. Most importantly, this compound is also expected to increase the efficacy of eltoprazine, a selective serotonin agonist currently under clinical investigation in dyskinetic patients.
In recent years, the serotonin system has emerged as a key player in dyskinesia. Here we show that the 5-HT1 receptor agonist eltoprazine and the serotonin precursor 5-Hydroxy-Tryptophan can elicit significant antidyskinetic effect in two different pre-clinical models of Parkinson’s disease. However, this treatment has also produced a reduction of the therapeutic effect of levodopa. Further work remains to be performed to understand whether this side effect is peculiar for the used compound or will extend to any drug with similar pharmacological profile.