The serotonergic system in motor and non-motor manifestations of Parkinson's disease

The understanding of Parkinson's disease (PD) classically revolves around dopamine depletion within the striatum. However, PD is a multi-systemic disease in which extra-dopaminergic systems are affected. The serotonergic (5-HT) system is one of these and has been extensively studied in PD. Although the 5-HT system uses one transporter (SERT) and 14 receptor sub-types, most of the studies in PD have focussed on SERT and serotonergic type 1A and 2A receptors (5-HT1A and 5-HT2A). Post-mortem autoradiographic binding studies and in vivo imaging studies have suggested an involvement of the 5-HT system in PD-related anxiety, depression, psychosis and L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia. Pre-clinical and clinical pharmacological studies have shown that SERT blockade might effectively alleviate depression and dyskinesia and, more recently, might exert disease-modifying effects. Enhancing the physiological activity of 5-HT1A receptors with 5-HT1A agonists might alleviate anxiety, dyskinesia and tremor, although a deleterious effect on the anti-parkinsonian efficacy of L-DOPA may ultimately limit the use of this class of compounds. Enhanced 5-HT2A-mediated neurotransmission has been associated with depression, dyskinesia, psychosis and tremor. The current article critically reviews studies assessing the SERT, as well as 5-HT1A and 5-HT2A receptors in idiopathic PD and animal models of PD, and discusses unmet challenges to effectively treat manifestations of PD using SERT antagonists, 5-HT1A agonists and 5-HT2A antagonists.