Modulation of 5-HT4R affects L-DOPA-induced dyskinesia in unilaterally 6-OHDA lesioned mice

Parkinson’s disease is caused by the selective loss of the dopaminergic neurons of the Substantia Nigra pars compacta and, consequently, striatal dopamine depletion. In Parkinson’s disease therapy, dopamine loss is counteracted by the administration of the dopamine precursor L-DOPA, which is initially effective in ameliorating motor symptoms, but over time it leads to a burdening side effect of uncontrollable jerky movements, termed L-DOPA-induced dyskinesia. To date, no efficient treatment for dyskinesia exists. The dopaminergic and serotonergic systems are intrinsically linked, and a role has been established in recent years for pre-synaptic 5-HT1a/b receptors in L-DOPA-induced dyskinesia. We hypothesized that post-synaptic serotonin receptors will also be affected by L-DOPA treatment and investigated the effect of modulation of 5-HT4 receptor on motor symptoms and L-DOPA-induced dyskinesia in the unilateral 6-OHDA mouse model of Parkinson’s disease. We show that modulation of the activity of this receptor impacts on LID but not on the anti-akinetic effect of L-DOPA. We further investigated the cellular expression pattern of the 5-HT4 receptor in the striatum and found the balance of activation of direct versus indirect medium spiny neurons by L-DOPA to be affected by the 5-HT4 receptor, in correspondence to its expression pattern. We propose that the post-synaptic serotonin receptor 5-HT4 may be a novel therapeutic target to reduce L-DOPA-induced dyskinesia.