What can we expect from the serotonergic side of L-DOPA?

Parkinson's disease has long been associated with neurodegeneration of the dopaminergic neurons located in the substantia nigra. The metabolic precursor L-DOPA, administered exogenously to patients, has proven its superiority over other medications. Yet, its effectiveness is altered after long-term use by diverse motor and non-motor symptoms. Knowledge of its mechanism of action would be necessary to better apprehend the side effects, but do we really know where and how it works? The connexion between L-DOPA and the serotonergic system, after a sort of crusade lasting for more than 40 years, has been acknowledged recently. The purpose of this review, mainly based on preclinical data, is to present the pharmacological and biochemical evidence demonstrating that serotonergic neurons are mainly involved in the enhancement of dopamine transmission induced by L-DOPA. We are addressing thereafter the two main expectations coming from this mechanism that are fundamental and clinical. The fundamental part will focus on the conceptual framework imposed by such a mechanism, questioning notably the notion that the benefit of L-DOPA is associated with a restoration of dopamine levels in the caudate-putamen. The clinical part will discuss serotonergic strategies to ameliorate the benefit of L-DOPA treatment in line with past and current clinical trials.