Dopamine release from serotonergic nerve fibers is reduced in L‐DOPA‐induced dyskinesia

Abstract

L-DOPA (3,4-dihydroxyphenyl-L-alanine) is the most commonly used treatment for symptomatic control in patients with Parkinson’s disease. Unfortunately, most patients develop severe side effects, such as dyskinesia, upon chronic L-DOPA treatment. The patophysiology of dyskinesia is unclear, however, involvement of serotonergic nerve fibers in converting L-DOPA to dopamine has been suggested. Therefore, potassium-evoked dopamine release was studied after local application of L-DOPA in the striata of normal, dopamine- and dopamine/serotonin-lesioned L-DOPA naïve, and dopamine-denervated chronically L-DOPA-treated dyskinetic rats using in vivo chronoamperometry. The results revealed that local L-DOPA administration into normal and intact hemisphere of dopamine-lesioned L-DOPA naïve animals significantly increased the potassium-evoked dopamine release. L-DOPA application also increased the dopamine peak amplitude in the dopamine-depleted L-DOPA naïve striatum, although these dopamine levels were several-folds lower than in the normal striatum, while no increased dopamine release was found in the dopamine/serotonin-denervated striatum. In dyskinetic animals, local L-DOPA application did not affect the dopamine release, resulting in significantly attenuated dopamine levels compared to those measured in L-DOPA naïve dopamine-denervated striatum. To conclude, L-DOPA is most likely converted to dopamine in serotonergic nerve fibers in the dopamine-depleted striatum, but the dopamine release is several-fold lower than in normal striatum. Furthermore, L-DOPA loading does not increase the dopamine release in dyskinetic animals as found in L-DOPA naïve animals, despite similar density of serotonergic innervation. Thus, the dopamine overflow produced from the serotonergic nerve fibers appears not to be the major cause of dyskinetic behavior.

Imaging DA release in a rat model of L-DOPA-induced dyskinesias: A longitudinal in vivo PET investigation of the antidyskinetic effect of MDMA

“…This is also in line with earlier findings from microdialysis experiments (Navailles et al, 2010;Tanaka et al, 1999). Because repeated L-DOPA administration has been shown to increase extracellular dopamine levels in microdialysis experiments (Carta et al, 2006;Miller and Abercrombie, 1999), the authors suggest that enhanced baseline levels of extracellular dopamine downregulate DA release via autoreceptor stimulation (Nevalainen et al, 2011). A similar mechanism might have occurred in our study as well, although we could not detect increased baseline DA concentrations after repeated L-DOPA treatment.…”

“…This was shown for the first time with PET and is in line with recent findings from in vivo chronoamperometry experiments on KCl-evoked extracellular dopamine release (Nevalainen et al, 2011) and in vivo microdialysis experiments (Navailles et al, 2011) after L-DOPA challenge in 6-OHDA lesioned rats before and after L-DOPA priming. Additionally, Nevalainen et al (2011) showed that DA in the DA-depleted striatum is released from serotonergic nerve fibers, because it disappeared after a serotonergic lesion. This is also in line with earlier findings from microdialysis experiments (Navailles et al, 2010;Tanaka et al, 1999).…”

“…These discrepancies are most likely a result of the different techniques used to measure DA release. While microdialysis measures basal extracellular DA levels, chronoamperometry-at least in the experiment performed by Nevalainen et al (2011)-measures KCl-evoked changes in DA concentrations that rise above the basal level. In contrast, with PET, DA is measured indirectly at baseline and under challenge conditions by competition with the D 2 receptor antagonist [ 11 C]raclopride.…”

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…5-HT terminals also participate in the reuptake of synaptic dopamine (Berger, 1978;Berger and Glowinski, 1978). Following degeneration of the nigrostriatal system, raphestriatal serotonergic terminals were demonstrated to release dopamine, which acts as a "false neurotransmitter," i.e., in an environment devoid of the autoregulatory mechanisms required for physiologic dopaminergic transmission, and this phenomenon was demonstrated to be a key determinant in the development and expression of LID (Carta et al, , 2008aNevalainen et al, 2011). Accordingly, in the 6-OHDA-lesioned rat, administration of L-DOPA to animals with dual lesions of the medial forebrain bundle and rostral raphe nucleus did not lead to the development of AIMs .…”

The highly-selective 5-HT1A agonist F15599 reduces l-DOPA-induced dyskinesia without compromising anti-parkinsonian benefits in the MPTP-lesioned macaque

“…Hence, false transmitter dopamine, synthesised from L-DOPA and released from serotonergic terminals, lacking the auto-regulatory mechanisms proper to dopaminergic terminals, is regarded as an important component of the pathophysiology of dyskinesia (Carta et al, 2007), although this view has been challenged (Nevalainen et al, 2011), and the contribution of the 5-HT system to L-DOPAinduced dyskinesia is still debated (Cenci, 2014). Abnormal glutamatergic transmission is also considered a key aetiological factor in dyskinesia (Huot et al, 2013a).…”