Pathophysiology of levodopa-induced dyskinesia: Insights from multimodal imaging and immunohistochemistry in non-human primates

Beaudoin-Gobert, Maude; Météreau, Élise; Duperrier, Sandra; Thobois, Stéphane; Tremblay, Léon; Sgambato-Faure, Véronique

doi:10.1016/j.neuroimage.2018.08.016

Cited by 17 publications

(10 citation statements)

References 64 publications

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“…The total loss of L-DOPA-induced DA release in the striatum of MPTP-treated monkeys after chronic L-DOPA injection is curious [70]. Even if the integrity of the 5-HT system was not addressed in this experiment, the lesion of 5-HT neurons induced by L-DOPA would be limited in dyskinetic monkeys [61,130]. In 6-OHDA rats, chronic administration of L-DOPA has been shown to reduce 5-HT tissue contents in the brain in some [51,131,132] but not all studies [57].…”

Section: Impairment Of Monoaminergic Transmissions By Trace Aminesmentioning

confidence: 98%

L-DOPA in Parkinson’s Disease: Looking at the “False” Neurotransmitters and Their Meaning

Chagraoui

Boulain

Juvin

et al. 2019

IJMS

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L-3,4-dihydroxyphenylalanine (L-DOPA) has been successfully used in the treatment of Parkinson’s disease (PD) for more than 50 years. It fulfilled the criteria to cross the blood–brain barrier and counteract the biochemical defect of dopamine (DA). It remarkably worked after some adjustments in line with the initial hypothesis, leaving a poor place to the plethora of mechanisms involving other neurotransmitters or mechanisms of action beyond newly synthesized DA itself. Yet, its mechanism of action is far from clear. It involves numerous distinct cell populations and does not mimic the mechanism of action of dopaminergic agonists. L-DOPA-derived DA is mainly released by serotonergic neurons as a false neurotransmitter, and serotonergic neurons are involved in L-DOPA-induced dyskinesia. The brain pattern and magnitude of DA extracellular levels together with this status of false neurotransmitters suggest that the striatal effects of DA via this mechanism would be minimal. Other metabolic products coming from newly formed DA or through the metabolism of L-DOPA itself could be involved. These compounds can be trace amines and derivatives. They could accumulate within the terminals of the remaining monoaminergic neurons. These “false neurotransmitters,” also known for some of them as inducing an “amphetamine-like” mechanism, could reduce the content of biogenic amines in terminals of monoaminergic neurons, thereby impairing the exocytotic process of monoamines including L-DOPA-induced DA extracellular outflow. The aim of this review is to present the mechanism of action of L-DOPA with a specific attention to “false neurotransmission.”

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Section: Impairment Of Monoaminergic Transmissions By Trace Aminesmentioning

confidence: 98%

L-DOPA in Parkinson’s Disease: Looking at the “False” Neurotransmitters and Their Meaning

Chagraoui

Boulain

Juvin

et al. 2019

IJMS

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“…30) Although these antagonists have been reported to provide up to 70% tic reduction, they have inadequate responses or intolerable side effects, such as dyskinesia. 31,32) Our data, showing that both SCH39166 and raclopride commonly changed the neuronal activations in the CP and ACB, suggests that D1 receptor antagonists may also treat tic disorders. In fact, recent clinical study shows that SCH39166, also called ecopipam, reduced tics and were well tolerated.…”

Section: Discussionmentioning

confidence: 77%

“…The severity of levodopainduced dyskinesia is correlated to serotonin transporter binding increases in the ventral striatum and ACC, which mediate motor function. 33) Thus, these shown differences in D1-and D2-receptor antagonists on neuronal networks may explain the clinical side effect differences.…”

Section: Discussionmentioning

confidence: 99%

Altered Functional Connectivity of the Orbital Cortex and Striatum Associated with Catalepsy Induced by Dopamine D1 and D2 Antagonists

Niu

Kasai

Seiriki

et al. 2021

Biological & Pharmaceutical Bulletin

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The dopamine system plays an important role in regulating many brain functions, including the motor function. The blockade of dopamine receptors results in a serious motor dysfunction, such as catalepsy and Parkinsonism. However, the neuronal mechanism underlying the drug-induced motor dysfunction is not well understood. Here, we examine brain-wide activation patterns in Fos-enhanced green fluorescent protein reporter mice that exhibit cataleptic behavior induced by SCH39166, a dopamine D1-like receptor antagonist, and raclopride, a dopamine D2-like receptor antagonist. Support vector classifications showed that the orbital cortex (ORB) and striatum including the caudoputamen (CP) and nucleus accumbens (ACB), prominently contribute to the discrimination between brains of the vehicle-treated and both SCH39166-and raclopride-treated mice. Interregional correlations indicated that the increased functional connectivity of functional networks, including the ORB, CP, and ACB, is the common mechanism underlying SCH39166and raclopride-induced cataleptic behavior. Moreover, the distinct mechanisms in the SCH39166-and raclopride-induced cataleptic behaviors are the decreased functional connectivity between three areas above and the cortical amygdala, and between three areas above and the anterior cingulate cortex, respectively. Thus, the alterations of functional connectivity in diverse brain regions, including the ORB, provide new insights on the mechanism underlying drug-induced movement disorders.

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“…Other studies provided further support about the key role of the serotonin in LID. Recent studies showed a selective regulation of 5-HT 1B serotonin receptor mRNA expression by L-DOPA treatment (Padovan-Neto et al, 2020), and dyskinetic monkeys and patients showed sprouting of serotonin terminals and increase in SERT levels (Rylander et al, 2010;Beaudoin-Gobert et al, 2018;Walker et al, 2019). BDNF overexpression increased the susceptibility to LID due to serotonin hyperinnervation (Tronci et al, 2017), and other recent studies further supported the role of BDNF in LID (Sanna et al, 2020).…”

Section: Involvement Of Serotonin In L-dopa-induced Dyskinesiasmentioning

confidence: 88%

Interactions Between the Serotonergic and Other Neurotransmitter Systems in the Basal Ganglia: Role in Parkinson’s Disease and Adverse Effects of L-DOPA

et al. 2020

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Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. However, other non-dopaminergic neuronal systems such as the serotonergic system are also involved. Serotonergic dysfunction is associated with non-motor symptoms and complications, including anxiety, depression, dementia, and sleep disturbances. This pathology reduces patient quality of life. Interaction between the serotonergic and other neurotransmitters systems such as dopamine, noradrenaline, glutamate, and GABA controls the activity of striatal neurons and are particularly interesting for understanding the pathophysiology of PD. Moreover, serotonergic dysfunction also causes motor symptoms. Interestingly, serotonergic neurons play an important role in the effects of L-DOPA in advanced PD stages. Serotonergic terminals can convert L-DOPA to dopamine, which mediates dopamine release as a "false" transmitter. The lack of any autoregulatory feedback control in serotonergic neurons to regulate L-DOPA-derived dopamine release contributes to the appearance of L-DOPA-induced dyskinesia (LID). This mechanism may also be involved in the development of graft-induced dyskinesias (GID), possibly due to the inclusion of serotonin neurons in the grafted tissue. Consistent with this, the administration of serotonergic agonists suppressed LID. In this review article, we summarize the interactions between the serotonergic and other systems. We also discuss the role of the serotonergic system in LID and if therapeutic approaches specifically targeting this system may constitute an effective strategy in PD.

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Pathophysiology of levodopa-induced dyskinesia: Insights from multimodal imaging and immunohistochemistry in non-human primates

Cited by 17 publications

References 64 publications

L-DOPA in Parkinson’s Disease: Looking at the “False” Neurotransmitters and Their Meaning

L-DOPA in Parkinson’s Disease: Looking at the “False” Neurotransmitters and Their Meaning

Altered Functional Connectivity of the Orbital Cortex and Striatum Associated with Catalepsy Induced by Dopamine D1 and D2 Antagonists

Interactions Between the Serotonergic and Other Neurotransmitter Systems in the Basal Ganglia: Role in Parkinson’s Disease and Adverse Effects of L-DOPA

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