Impairment of Serotonergic Transmission by the Antiparkinsonian Drug L-DOPA: Mechanisms and Clinical Implications

Abstract

The link between the anti-Parkinsonian drug L-3,4-dihydroxyphenylalanine (L-DOPA) and the serotonergic (5-HT) system has been long established and has received increased attention during the last decade. Most studies have focused on the fact that L-DOPA can be transformed into dopamine (DA) and released from 5-HT terminals, which is especially important for the management of L-DOPA-induced dyskinesia. In patients, treatment using L-DOPA also impacts 5-HT neurotransmission; however, few studies have investigated the mechanisms of this effect. The purpose of this review is to summarize the electrophysiological and neurochemical data concerning the effects of L-DOPA on 5-HT cell function. This review will argue that L-DOPA disrupts the link between the electrical activity of 5-HT neurons and 5-HT release as well as that between 5-HT release and extracellular 5-HT levels. These effects are caused by the actions of L-DOPA and DA in 5-HT neurons, which affect 5-HT neurotransmission from the biosynthesis of 5-HT to the impairment of the 5-HT transporter. The interaction between L-DOPA and 5-HT transmission is especially relevant in those Parkinson's disease (PD) patients that suffer dyskinesia, comorbid anxiety or depression, since the efficacy of antidepressants or 5-HT compounds may be affected.

Keywords: Parkinson’s disease; depression; dopamine; dyskinesia; electrophysiology; exocytosis; intracerebral microdialysis; serotonin.

Figure 1

Region-dependent effects of L-3,4-dihydroxyphenylalanine (L-DOPA) on serotonin (5-HT) extracellular levels in some brain regions. L-DOPA acts at the level of 5-HT cell bodies in the dorsal raphe nucleus (DRN) and 5-HT terminals in the brain including the prefrontal cortex, the hippocampus, the striatum or the substantia nigra pars reticulate. While L-DOPA triggers an increase in dopamine (DA) release in all regions, it inhibits 5-HT release in the substantia nigra reticulata, the prefrontal cortex and presumably in the DRN, induces biphasic effects (Δ) in the hippocampus and merely affects 5-HT release in the striatum. The changes in DA and 5-HT extracellular levels occur without any modification of 5-HT neuron activity. HIPP, hippocampus; PFC, prefrontal cortex; STR, striatum; SNr, substantia nigra reticulate.

Figure 2

Competition between L-DOPA-derived dopamine (DA) and serotonin (5-HT) inside 5-HT neurons. L-DOPA competes with 5-HTP for AADC to synthesize DA and 5-HT, respectively. DA competes with 5-HT in terms of VMAT2-mediated packaging of exocytotic vesicles. In consequence, intracellular 5-HT levels can transiently rise and 5-HT can exit the neuron via SERT in a non-exocytotic manner. This 5-HT output can only be observed under specific conditions, as L-DOPA-derived DA can also alter the function of SERT. First, extracellular DA can undergo reuptake by SERT, reducing the 5-HT flow through this transporter. Second, intracellular DA can also enter the neuron through the SERT, impairing the output of 5-HT. In the cytoplasm, MAO can more efficiently degrade DA than 5-HT, increasing oxidative metabolism and aldehyde derivates. These biochemical events occur with no modification of the firing rate of 5-HT neurons. AADC, amino acid decarboxylase, L-DOPA, 3,4-Dihydroxyphenylacetaldehyde; MAO, monoamine oxidase; SERT, serotonin transporter; VMAT2, monoamine vesicular transporter; 5-HIAAL, 5-hydroxyindole acetaldehyde; 5-HTP, 5-hydroxytryptophan.