Predicting Dopaminergic Effects of L‐DOPA in the Treatment for Parkinson's Disease

Abstract

Numerous advances have been made in the understanding of the mechanism of action of the antiparkinsonian medicine L-DOPA. This has allowed for the development of interesting predictive models regarding the positive and side effects of this medication. Recently, a mathematical model has been developed to investigate the impact of L-DOPA on dopamine (DA) release from serotonergic (5-HT) terminals in the striatum [1]. The parameters used to elaborate this model were partially based on experimental data and may not be sufficient to illustrate the biochemical effects of L-DOPA inside 5-HT terminals. Parkinson’s disease, the second most devastating neurodegenerative disease in terms of prevalence, has benefited from efficient treatments for 50 years. The disease is characterized by the progressive loss of mesencephalic DA neurons from the substantia nigra pars compacta innervating the striatum [2]. L-DOPA, the precursor of DA, was introduced in the mid-60s to limit the decrease in DA associated with the degeneration of DA neurons. Upon chronic use of L-DOPA, numerous side effects emerged such as L-DOPA-induced dyskinesia (LID). Among the various theories on LID [3,4], the presynaptic hypothesis postulates that the increase in DA release induced by L-DOPA is directly implicated in LID [5]. After several years of skepticism, it is now accepted that 5-HT neurons are mainly responsible for the release of DA induced by L-DOPA [6]. 5-HT neurons are also responsible for the behavioral effects of L-DOPA including locomotor activity, LID, and cognitive effects [7]. Thus, the activity of 5-HT neurons has become the most relevant parameter in predicting the DA output of L-DOPA. The model by Reed et al. (2012) focuses on the consequences of the import of L-DOPA into 5-HT neurons on DA and 5-HT releases in the striatum. The main biochemical effects of L-DOPA inside 5-HT terminals allowed the authors to predict the shortening of the L-DOPA therapeutic window and the synergistic benefit of 5-HT1A and 5-HT1B agonists against LIDs. So far, this mathematical model closely approximates the mechanism of action of L-DOPA and raises interesting hypothesis that can be tested experimentally. Nevertheless, significant experimental findings dampen the full validity of the model. They concern the function of the striatal 5-HT terminal itself in the presence of L-DOPA and the ectopic influence of L-DOPA-derived DA release in the Parkinsonian brain. First, the mechanisms triggered by L-DOPA to enhance DA extracellular levels from striatal 5-HT terminals may not be directly related to the firing rate of 5-HT neurons. The main portion of L-DOPA-induced DA release comes from 5-HT neurons [6], but the mechanism is not entirely impulse-dependent [8,9] (Figure 1). Indeed, L-DOPA may trigger a nonexocytotic release of DA via the reversal of 5-HT uptake sites [6]. This may explain why the dampening effect of 5-HT1A agonist alone or in combination with a 5-HT1B agonist on L-DOPA-induced striatal DA release is only partial [8,10]. Moreover, the dampening effect of a 5-HT1B agonist alone on L-DOPA-induced striatal DA release has not yet been reported [10]. Consequently, the control of the electrical activity of 5-HT neurons does not exclude the output of DA from 5-HT terminals. It is also noteworthy that LID is not related to a higher striatal DA release compared with non-dyskinetic animals