Dysfunction of serotonergic neurons in Parkinson's disease and dyskinesia

Vegas-Suárez, Sergio; Paredes-Rodriguez, Elena; Aristieta, Asier; Lafuente, José Vicente; Miguélez, Cristina; Ugedo, Luisa

doi:10.1016/bs.irn.2019.06.013

Cited by 20 publications

(18 citation statements)

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“…Published studies regarding SERT and 5‐HT 1A receptor changes in Parkinson's disease have provided contradictory results showing increased, decreased or unmodified expression of these proteins both in humans and in animal models. This discrepancy may be due to the stage of the disease, the treatment, or the experimental model used (for review, see Vegas‐Suarez et al, 2019). To better explain our electrophysiological and microdialysis results, we performed immunohistochemical detection of SERT and 5‐HT 1A in the same experimental model.…”

Section: Discussionmentioning

confidence: 99%

“…When investigating the possible effect of antidyskinetic drugs, it is important to take into account the results collected in animal models of Parkinson's disease that reveal the structural and functional changes in the 5‐HT system induced by DA depletion and/or chronic administration of l ‐DOPA (see review Vegas‐Suarez et al, 2019). In this regard, we have observed that buspirone, a 5‐HT 1A receptor partial agonist, inhibits neuronal activity in the subthalamic nucleus in control rats but has no effect after DA depletion (Sagarduy et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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6‐Hydroxydopamine lesion and levodopa treatment modify the effect of buspirone in the substantia nigra pars reticulata

Vegas-Suárez

Pisanò

Requejo

et al. 2020

British J Pharmacology

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Background and Purpose l‐DOPA‐induced dyskinesia (LID) is considered a major complication in the treatment of Parkinson's disease (PD). Buspirone (5‐HT1A partial agonist) have shown promising results in the treatment of PD and LID, however no 5‐HT‐based treatment has been approved in PD. The present study was aimed to investigate how the substantia nigra pars reticulata (SNr) is affected by buspirone and whether it is a good target to study 5‐HT antidyskinetic treatments. Experimental Approach Buspirone was studied using in vivo single‐unit, electrocorticogram, local field potential recordings along with microdialysis and immunohistochemistry in naïve/sham, 6‐hydroxydopamine (6‐OHDA)‐lesioned or 6‐OHDA‐lesioned and l‐DOPA‐treated (6‐OHDA/l‐DOPA) rats. Key Results Local buspirone inhibited SNr neuron activity in all groups. However, systemic buspirone reduced burst activity in 6‐OHDA‐lesioned rats (with or without l‐DOPA treatment), whereas 8‐OH‐DPAT, a full 5‐HT1A agonist induced larger inhibitory effects in sham animals. Neither buspirone nor 8‐OH‐DPAT markedly modified the low‐frequency oscillatory activity in the SNr or synchronization within the SNr with the cortex. In addition, local perfusion of buspirone increased GABA and glutamate release in the SNr of naïve and 6‐OHDA‐lesioned rats but no effect in 6‐OHDA/l‐DOPA rats. In the 6‐OHDA/l‐DOPA group, increased 5‐HT transporter and decreased 5‐HT1A receptor expression was found. Conclusions and Implications The effects of buspirone in SNr are influenced by dopamine loss and l‐DOPA treatment. The present results suggest that the regulation of burst activity of the SNr induced by DA loss may be a good target to test new drugs for the treatment of PD and LID.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

6‐Hydroxydopamine lesion and levodopa treatment modify the effect of buspirone in the substantia nigra pars reticulata

Vegas-Suárez

Pisanò

Requejo

et al. 2020

British J Pharmacology

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“…In addition to the dopaminergic system, it has been compellingly demonstrated that the serotonergic system is involved in the pathophysiology of Parkinson's disease, whether in terms of motor symptoms [24]; [42] or non-motor symptoms such as cognitive impairment [43] and mood disorders [44], but also in the etiology of LID [45,46]. In this context, the 5-HT1AR appears to be a promising therapeutic target: in addition to having a potential therapeutic effect in treating motor [47][48][49][50] and cognitive [51] symptoms or mood disorders [52][53][54][55] associated with Parkinson's disease, 5-HT1A agonists are highly effective for treating LID in preclinical models [13,14,16,18,[56][57][58][59][60][61].…”

Section: -Ht1ar As a Promising Therapeutic Target For Parkinson's Disease?mentioning

confidence: 99%

Different Alterations of Agonist and Antagonist Binding to 5-HT1A Receptor in a Rat Model of Parkinson’s Disease and Levodopa-Induced Dyskinesia: A MicroPET Study

Vidal

Levigoureux

Chaib

et al. 2021

JPD

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Background: The gold-standard treatment for Parkinson’s disease is L-DOPA, which in the long term often leads to levodopa-induced dyskinesia. Serotonergic neurons are partially responsible for this, by converting L-DOPA into dopamine before uncontrolled release as a “false neurotransmitter”. The stimulation of 5-HT1A receptors can reduce involuntary movements but this mechanism is poorly understood. Objective: This study aimed to investigate the functionality of 5-HT1A receptor using positron emission tomography in hemiparkinsonian rats with or without dyskinesia induced by 3-weeks daily treatment with L-DOPA. Imaging sessions were performed “off” L-DOPA. Methods: Each rat underwent a positron emission tomography scan with [18F]F13640, a 5-HT1AR agonist (which labels receptors in a high affinity state for agonists) or [18F]MPPF, a 5-HT1AR antagonist (which labels all the receptors). Results: There were decreases of [18F]MPPF binding in hemiparkinsonian rats in cortical areas. In dyskinetic animals, changes were slighter but also found in other regions. In hemiparkinsonian rats, [18F]F13640 uptake was decreased in the globus pallidus and thalamus. On the contralateral side, binding was increased in the insula, the hippocampus and the amygdala. In dyskinetic animals, [18F]F13640 binding was strongly increased in cortical and limbic areas, especially in the non-lesioned side. Conclusion: These data suggest that agonist and antagonist 5-HT1A receptor-binding sites are differently modified in Parkinson’s disease and levodopa-induced dyskinesia. In particular, these observations suggest an important involvement of the functional state of 5-HT1AR in levodopa-induced dyskinesia and emphasize the need to characterize this state using agonist radiotracers in physiological and pathological conditions.

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“…Serotonin is a monoamine with an integral role in the human body not only as a neurotransmitter in the central nervous system, but also as a signaling molecule in the periphery [1]. It is important in many different aspects of brain activity, such as mood, memory, emotion, sleep, appetite, and motor activity [2]. Serotonin has a crucial role in the periphery as well, especially in the gastrointestinal system as 90% of total serotonin in the body is produced in the enterochromaffin cells, where it controls intestinal movement [3].…”

Section: Introductionmentioning

confidence: 99%

“…Serotonergic neurotransmission is widely distributed in the brain and is mediated by serotonergic neurons in the raphe nuclei [5]. These neurons project to the striatum, which possesses all the machinery of the serotonergic pathway [2], meaning that serotonergic and dopaminergic pathways overlap greatly [6]. Alpha-synuclein, the misfolded protein deposited in the brain of PD patients, can be found not only in dopaminergic neurons, but in serotonergic neurons of raphe nuclei as well.…”

Section: Introductionmentioning

confidence: 99%

Serotonin-Related Functional Genetic Variants Affect the Occurrence of Psychiatric and Motor Adverse Events of Dopaminergic Treatment in Parkinson’s Disease: A Retrospective Cohort Study

Redenšek

Blagus

Trošt

et al. 2022

JPM

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The serotonergic system is important in Parkinson’s disease (PD) pathogenesis as it can take over dopamine production after a large portion of dopaminergic neurons is lost through neurodegeneration. The aim of this study was to evaluate the effect of genetic variability of serotonergic genes on the occurrence of motor complications and psychiatric adverse events (AE) due to dopaminergic treatment. We enrolled 231 patients and their clinical data were collected. Genotyping was performed for eight genetic variants. Logistic regression was used for analysis. Carriers of the HTR1A rs6295 GC genotype (OR = 2.58; 95% CI = 1.15–5.78; p = 0.021), TPH2 rs4290270 AA genotype (OR = 2.78; 95% CI = 1.08–7.03; p = 0.034), and at least one TPH2 rs4570625 T allele (OR = 1.86; 95% CI = 1.00–3.44; p = 0.047) had increased risk for visual hallucinations (VH). Additionally, carriers of at least one SLC6A4 5-HTTPLR rs25531 S (OR = 0.52; 95% CI = 0.28–0.96; p = 0.037) or at least one LG allele (OR = 0.37; 95% CI = 0.14–0.97; p = 0.044) had a decreased chance for VH. Constructed haplotypes of the TPH2 showed increased risk for VH (OR = 1.94; 95% CI = 1.06–3.55; p = 0.032) and impulse control disorders (OR = 5.20; 95% CI = 1.86–14.50; p = 0.002). Finally, individual gene–gene interactions showed decreased odds for the development of motor AE. Our findings suggest that the serotonergic pathway may play an important role in the development of AE resulting from dopaminergic treatment.

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Dysfunction of serotonergic neurons in Parkinson's disease and dyskinesia

Cited by 20 publications

References 100 publications

6‐Hydroxydopamine lesion and levodopa treatment modify the effect of buspirone in the substantia nigra pars reticulata

6‐Hydroxydopamine lesion and levodopa treatment modify the effect of buspirone in the substantia nigra pars reticulata

Different Alterations of Agonist and Antagonist Binding to 5-HT1A Receptor in a Rat Model of Parkinson’s Disease and Levodopa-Induced Dyskinesia: A MicroPET Study

Serotonin-Related Functional Genetic Variants Affect the Occurrence of Psychiatric and Motor Adverse Events of Dopaminergic Treatment in Parkinson’s Disease: A Retrospective Cohort Study

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