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Lipari N, Galfano A, Venkatesh S, Grezenko H, Sandoval IM, Manfredsson FP, Bishop C. The effects of chemogenetic targeting of serotonin-projecting pathways on L-DOPA-induced dyskinesia and psychosis in a bilateral rat model of Parkinson's disease. Front Neural Circuits 2024; 18:1463941. [PMID: 39634948 PMCID: PMC11615880 DOI: 10.3389/fncir.2024.1463941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 10/07/2024] [Indexed: 12/07/2024] Open
Abstract
Introduction Parkinson's disease (PD) is commonly characterized by severe dopamine (DA) depletion within the substantia nigra (SN) leading to a myriad of motor and non-motor symptoms. One underappreciated and prevalent non-motor symptom, Parkinson's disease-associated psychosis (PDAP), significantly erodes patient and caregiver quality of life yet remains vastly understudied. While the gold standard pharmacotherapy for motor symptoms Levodopa (LD) is initially highly effective, it can lead to motor fluctuations like LD-induced dyskinesia (LID) and non-motor fluctuations such as intermittent PDAP. One source of these fluctuations could be the serotonergic raphe nuclei and their projections. Serotonin (5-HT) neurons possess the machinery necessary to convert and release DA from exogenous LD. In DA-depleted brain regions these 5-HT projections can act as surrogates to the DA system initially compensating but chronically leading to aberrant neuroplasticity which has been linked to LID and may also contribute to non-motor fluctuations. In support, recent work from our lab established a positive relationship between LID and PDAP in parkinsonian rats. Therefore, it was hypothesized that normalizing 5-HT forebrain input would reduce the co-expression of LID and PDAP. Methods To do so, we expressed 5-HT projection specific inhibitory designer receptor exclusively activated by designer drugs (DREADDs) using Cre-dependent AAV9-hM4di in tryptophan hydroxylase 2 (TPH2)-Cre bilaterally 6-OHDA-lesioned rats. Thereafter we used the designer drug Compound 21 to selectively inhibit 5-HT raphe projections during LD treatment to modulate the expression of PDAP, assayed by prepulse inhibition (PPI) and LID, quantified by the abnormal involuntary movements (AIMs) test. Results Our results suggest that chemogenetic inhibition of 5-HT raphe-projecting cells significantly reduces LID without affecting stepping ability or established sensorimotor gating deficits. Discussion Overall, this study provides further evidence for the complex influence of 5-HT raphe-projecting neurons on LD's neurobehavioral effects.
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Affiliation(s)
- Natalie Lipari
- Department of Psychology, Binghamton University, Binghamton, NY, United States
| | - Ashley Galfano
- Department of Psychology, Binghamton University, Binghamton, NY, United States
| | - Shruti Venkatesh
- Department of Psychology, Binghamton University, Binghamton, NY, United States
| | - Han Grezenko
- Barrow Neurological Institute, Phoenix, AZ, United States
| | | | | | - Christopher Bishop
- Department of Psychology, Binghamton University, Binghamton, NY, United States
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Frouni I, Kwan C, Bédard D, Kang W, Hamadjida A, Nuara SG, Gourdon JC, Huot P. Effect of the mGlu 4 positive allosteric modulator ADX-88178 on parkinsonism, psychosis-like behaviours and dyskinesia in the MPTP-lesioned marmoset. Psychopharmacology (Berl) 2023; 240:2093-2099. [PMID: 37516708 DOI: 10.1007/s00213-023-06428-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 07/17/2023] [Indexed: 07/31/2023]
Abstract
RATIONALE Positive allosteric modulation of metabotropic glutamate type 4 (mGlu4) receptors is a promising strategy to alleviate parkinsonian disability and L-3,4-dihydroxyphenylalanine (L-DOPA) induced dyskinesia. ADX-88178 is a highly selective mGlu4 positive allosteric modulator (PAM) that previously enhanced the anti-parkinsonian action of L-DOPA in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease (PD). OBJECTIVES We sought to explore the effects of ADX-88178 on psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. We also aimed to determine the effect of ADX-88178 on parkinsonism and dyskinesia. METHODS Six MPTP-lesioned marmosets were administered L-DOPA chronically to induce stable PLBs and dyskinesias. They were then administered ADX-88178 (0.01, 0.1 and 1 mg/kg) or vehicle, in combination with L-DOPA/benserazide (15/3.75 mg/kg), both sub-cutaneously, in a randomised fashion. PLBs, parkinsonism and dyskinesia were then measured. RESULTS ADX-88178 mildly worsened global PLBs at the dose of 1 mg/kg (by 13%, P = 0.020). L-DOPA alone conferred 158 min of on-time, while the duration of on-time was 212 min (34% increase, P = 0.011), after adding ADX-88178 1 mg/kg to L-DOPA. Accordingly, ADX-88178 1 mg/kg reduced global parkinsonian disability, by 38% (P = 0.0096). ADX-88178 1 mg/kg diminished peak dose dyskinesia by 34% (P = 0.015). Minimal effects were provided by lower doses. CONCLUSIONS Whereas these results provide additional evidence of the anti-parkinsonian and anti-dyskinetic effects of mGlu4 positive allosteric modulation as an adjunct to L-DOPA, they also suggest that ADX-88178 may exacerbate dopaminergic psychosis. Further studies are needed to evaluate this possible adverse effect of mGlu4 PAMs on PD psychosis.
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Affiliation(s)
- Imane Frouni
- Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), 3801 University St, Montreal, QC, Canada
- Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada
| | - Cynthia Kwan
- Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), 3801 University St, Montreal, QC, Canada
| | - Dominique Bédard
- Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), 3801 University St, Montreal, QC, Canada
| | - Woojin Kang
- Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), 3801 University St, Montreal, QC, Canada
| | - Adjia Hamadjida
- Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), 3801 University St, Montreal, QC, Canada
| | - Stephen G Nuara
- Comparative Medicine & Animal Resource Centre, McGill University, Montreal, QC, Canada
| | - Jim C Gourdon
- Comparative Medicine & Animal Resource Centre, McGill University, Montreal, QC, Canada
| | - Philippe Huot
- Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), 3801 University St, Montreal, QC, Canada.
- Département de Pharmacologie et Physiologie, Université de Montréal, Montreal, QC, Canada.
- Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
- Movement Disorder Clinic, Division of Neurology, Department of Neurosciences, McGill University Health Centre, Montreal, QC, Canada.
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Lipari N, Centner A, Glinski J, Cohen S, Manfredsson FP, Bishop C. Characterizing the relationship between L-DOPA-induced-dyskinesia and psychosis-like behaviors in a bilateral rat model of Parkinson's disease. Neurobiol Dis 2023; 176:105965. [PMID: 36526089 DOI: 10.1016/j.nbd.2022.105965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/30/2022] [Accepted: 12/12/2022] [Indexed: 12/15/2022] Open
Abstract
Parkinson's disease associated psychosis (PDAP) is a prevalent non-motor symptom (NMS) that significantly erodes patients' and caregivers' quality of life yet remains vastly understudied. One potential source of PDAP in late-stage Parkinson's disease (PD) is the common dopamine (DA) replacement therapy for motor symptoms, Levodopa (L-DOPA). Given the high incidence of L-DOPA-induced dyskinesia (LID) in later phases of PD, this study sought to characterize the relationship between PDAP and LID in a bilateral medial forebrain bundle 6-hydroxydopamine hydrobromide (6-OHDA) lesion rat model. To assess PDAP in this model, prepulse inhibition (PPI), a well-validated assay of sensorimotor gating, was employed. First, we tested whether a bilateral lesion alone or after chronic L-DOPA treatment was sufficient to induce PPI dysfunction. Rats were also monitored for LID development, using the abnormal involuntary movements (AIMs) test, to examine PPI and LID associations. In experiment 2, Vilazodone (VZD), a serotonin transporter (SERT) blocker and 1A receptor (5-HT1A) partial agonist was administered to test its potential efficacy in reducing LID and PPI dysfunction. Once testing was complete, tissue was collected for high performance liquid chromatography (HPLC) to examine the monoamine levels in motor and non-motor circuits. Results indicate that bilateral DA lesions produced motor deficits and that chronic L-DOPA induced moderate AIMs; importantly, rats that developed more severe AIMs were more likely to display sensorimotor gating dysfunction. In addition, VZD treatment dose-dependently reduced L-DOPA-induced AIMs without impairing L-DOPA efficacy, although VZD's effects on PPI were limited. Altogether, this project established the bilateral 6-OHDA lesion model accurately portrayed LID and PDAP-like behaviors, uncovered their potential relationship, and finally, demonstrated the utility of VZD for reducing LID.
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Affiliation(s)
- Natalie Lipari
- Department of Psychology, Binghamton University, Binghamton, NY, USA
| | - Ashley Centner
- Department of Psychology, Binghamton University, Binghamton, NY, USA
| | - John Glinski
- Department of Psychology, Binghamton University, Binghamton, NY, USA
| | - Sophie Cohen
- Department of Psychology, Binghamton University, Binghamton, NY, USA
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Zhang S, Ma Y. Emerging role of psychosis in Parkinson's disease: From clinical relevance to molecular mechanisms. World J Psychiatry 2022; 12:1127-1140. [PMID: 36186499 PMCID: PMC9521528 DOI: 10.5498/wjp.v12.i9.1127] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 06/12/2022] [Accepted: 08/16/2022] [Indexed: 02/05/2023] Open
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease. Psychosis is one of the common psychiatric presentations in the natural course of PD. PD psychosis is an important non-motor symptom, which is strongly correlated with a poor prognosis. Increasing attention is being given to PD psychosis. In this opinion review, we summarized and analyzed the identification, screening, epidemiology, mechanisms, risk factors, and therapeutic approaches of PD psychosis based on the current clinical evidence. PD psychosis tends to have a negative effect on patients' quality of life and increases the burden of family caregiving. Screening and identification in the early stage of disease is crucial for establishing tailored therapeutic strategies and predicting the long-term outcome. Development of PD psychosis is believed to involve a combination of exogenous and endogenous mechanisms including imbalance of neurotransmitters, structural and network changes, genetic profiles, cognitive impairment, and antiparkinsonian medications. The therapeutic strategy for PD psychosis includes reducing or ceasing the use of dopaminergic drug, antipsychotics, cholinesterase inhibitors, and non-pharmacological interventions. Ongoing clinical trials are expected to provide new insights for tailoring therapy for PD psychosis. Future research based on novel biomarkers and genetic factors may help inform individualized therapeutic strategies.
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Affiliation(s)
- Shuo Zhang
- Department of Neurology, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Yan Ma
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
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Vidal B, Levigoureux E, Chaib S, Bouillot C, Billard T, Newman-Tancredi A, Zimmer L. 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. JOURNAL OF PARKINSONS DISEASE 2021; 11:1257-1269. [DOI: 10.3233/jpd-212580] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
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 leading to its 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 receptors 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 with [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 bilaterally in the globus pallidus and thalamus. On the non-lesioned 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 a substantial 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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Affiliation(s)
- Benjamin Vidal
- Lyon Neuroscience Research Center, Université de Lyon, Université Claude Bernard Lyon 1, CNRS, INSERM, Lyon, France
| | - Elise Levigoureux
- Lyon Neuroscience Research Center, Université de Lyon, Université Claude Bernard Lyon 1, CNRS, INSERM, Lyon, France
- Hospices Civils de Lyon, Lyon, France
| | - Sarah Chaib
- Lyon Neuroscience Research Center, Université de Lyon, Université Claude Bernard Lyon 1, CNRS, INSERM, Lyon, France
- Hospices Civils de Lyon, Lyon, France
| | | | - Thierry Billard
- CERMEP-Imaging Platform, Bron, France
- Institute of Chemistry and Biochemistry, Université de Lyon, CNRS, Villeurbanne, France
| | | | - Luc Zimmer
- Lyon Neuroscience Research Center, Université de Lyon, Université Claude Bernard Lyon 1, CNRS, INSERM, Lyon, France
- Hospices Civils de Lyon, Lyon, France
- CERMEP-Imaging Platform, Bron, France
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Vegas‐Suárez S, Aristieta A, Requejo C, Bengoetxea H, Lafuente JV, Miguelez C, Ugedo L. The effect of 5-HT 1A receptor agonists on the entopeduncular nucleus is modified in 6-hydroxydopamine-lesioned rats. Br J Pharmacol 2021; 178:2516-2532. [PMID: 33686657 PMCID: PMC8252460 DOI: 10.1111/bph.15437] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 02/24/2021] [Accepted: 03/01/2021] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND AND PURPOSE l-DOPA prolonged treatment leads to disabling motor complications as dyskinesia that could be decreased by drugs acting on 5-HT1A receptors. Since the internal segment of the globus pallidus, homologous to the entopeduncular nucleus in rodents, seems to be involved in the etiopathology of l-DOPA-induced dyskinesia, we investigated whether the entopeduncular nucleus is modulated by the 5-HT1A receptor partial and full agonists, buspirone, and 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) in control and 6-hydroxydopamine (6-OHDA)-lesioned rats with or without long-term l-DOPA treatment. EXPERIMENTAL APPROACH Extracellular single-unit electrocorticogram and local field potential recordings under anaesthesia, immunostaining assays and optogenetic manipulation coupled to electrophysiological recordings were performed. KEY RESULTS Systemic buspirone reduced the entopeduncular nucleus firing rate in the sham animals and burst activity in the 6-OHDA-lesioned rats (with or without l-DOPA treatment), while local administration reduced entopeduncular nucleus activity in all the groups, regardless of DA integrity. Systemic 8-OH-DPAT also induced inhibitory effects only in the sham animals. Effects triggered by buspirone and 8-OH-DPAT were reversed by the 5-HT1A receptor antagonist, WAY-100635. Neither buspirone nor 8-OH-DPAT modified the low-frequency oscillatory activity in the entopeduncular nucleus or its synchronization with the motor cortex. Buspirone did not alter the response induced by subthalamic nucleus opto-stimulation in the entopeduncular nucleus. CONCLUSION AND IMPLICATIONS Systemic 5-HT1A receptor activation elicits different effects on the electrophysiological properties of the entopeduncular nucleus depending on the integrity of the nigrostriatal pathway and it does not alter the relationship between subthalamic nucleus and entopeduncular nucleus neuron activity.
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Affiliation(s)
- Sergio Vegas‐Suárez
- Department of Pharmacology, Faculty of Medicine and NursingUniversity of the Basque Country (UPV/EHU)LeioaSpain
- Autonomic and Movement Disorders Unit, Neurodegenerative DiseasesBiocruces Health Research InstituteBarakaldoSpain
| | - Asier Aristieta
- Department of Biological SciencesCarnegie Mellon UniversityPittsburghPAUSA
- Center for the Neural Basis of CognitionCarnegie Mellon UniversityPittsburghPAUSA
| | - Catalina Requejo
- LaNCE, Department of NeuroscienceUniversity of the Basque Country (UPV/EHU)LeioaSpain
| | - Harkaitz Bengoetxea
- LaNCE, Department of NeuroscienceUniversity of the Basque Country (UPV/EHU)LeioaSpain
| | - José Vicente Lafuente
- LaNCE, Department of NeuroscienceUniversity of the Basque Country (UPV/EHU)LeioaSpain
| | - Cristina Miguelez
- Department of Pharmacology, Faculty of Medicine and NursingUniversity of the Basque Country (UPV/EHU)LeioaSpain
- Autonomic and Movement Disorders Unit, Neurodegenerative DiseasesBiocruces Health Research InstituteBarakaldoSpain
| | - Luisa Ugedo
- Department of Pharmacology, Faculty of Medicine and NursingUniversity of the Basque Country (UPV/EHU)LeioaSpain
- Autonomic and Movement Disorders Unit, Neurodegenerative DiseasesBiocruces Health Research InstituteBarakaldoSpain
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7
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Vegas-Suarez S, Paredes-Rodriguez E, Aristieta A, Lafuente JV, Miguelez C, Ugedo L. Dysfunction of serotonergic neurons in Parkinson's disease and dyskinesia. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2019; 146:259-279. [PMID: 31349930 DOI: 10.1016/bs.irn.2019.06.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra, the depletion of striatal dopamine and the presence of Lewy aggregates containing alpha-synuclein. Clinically, there are motor impairments involving cardinal movement symptoms, bradykinesia, resting tremor, muscle rigidity, and postural abnormalities, along with non-motor symptoms such as sleep, behavior and mood disorders. The current treatment for PD focuses on restoring dopaminergic neurotransmission by l-3,4-dihydroxyphenylalanine (levodopa), which loses therapeutic efficacy and induces disabling abnormal involuntary movements known as levodopa-induced dyskinesia (LID) after several years. Evidence indicates that the pathophysiology of both PD and LID disorders is also associated with the dysfunctional activity of the serotonergic (5-HT) neurons that may be responsible for motor and non-motor disturbances. The main population of 5-HT neurons is located in the dorsal raphe nuclei (DRN), which provides extensive innervation to almost the entire neuroaxis and controls multiple functions in the brain. The degeneration of DRN 5-HT neurons occurs in early PD. These neurons can also take exogenous levodopa to transform it into dopamine, which may disturb neuron activity. This review will provide an overview of the underlying mechanisms responsible for 5-HT dysfunction and its clinical relevance in PD and dyskinesia.
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Affiliation(s)
- Sergio Vegas-Suarez
- Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain; Neurodegenerative Diseases, Biocruces Health Research Institute, Barakaldo, Spain
| | - Elena Paredes-Rodriguez
- Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain; Neurodegenerative Diseases, Biocruces Health Research Institute, Barakaldo, Spain
| | - Asier Aristieta
- Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; Centre National de la Recherche Scientifique, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France
| | - Jose V Lafuente
- Department of Neurosciences, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain; Nanosurgery, Biocruces Health Research Institute, Barakaldo, Spain
| | - Cristina Miguelez
- Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain; Neurodegenerative Diseases, Biocruces Health Research Institute, Barakaldo, Spain
| | - Luisa Ugedo
- Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain; Neurodegenerative Diseases, Biocruces Health Research Institute, Barakaldo, Spain.
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8
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Yousaf T, Wilson H, Politis M. Imaging the Nonmotor Symptoms in Parkinson's Disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2017; 133:179-257. [PMID: 28802921 DOI: 10.1016/bs.irn.2017.05.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Parkinson's disease is acknowledged to be a multisystem syndrome, manifesting as a result of multineuropeptide dysfunction, including dopaminergic, cholinergic, serotonergic, and noradrenergic deficits. This multisystem disorder ultimately leads to the presentation of a range of nonmotor symptoms, now appreciated to be an integral part of the disease-specific spectrum of symptoms, often preceding the diagnosis of motor Parkinson's disease. In this chapter, we review the dopaminergic and nondopaminergic basis of these symptoms by exploring the neuroimaging evidence based on several techniques including positron emission tomography, single-photon emission computed tomography molecular imaging, magnetic resonance imaging, functional magnetic resonance imaging, and diffusion tensor imaging. We discuss the role of these neuroimaging techniques in elucidating the underlying pathophysiology of NMS in Parkinson's disease.
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Affiliation(s)
- Tayyabah Yousaf
- Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom
| | - Heather Wilson
- Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom
| | - Marios Politis
- Neurodegeneration Imaging Group, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London, London, United Kingdom.
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9
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Huot P, Sgambato-Faure V, Fox SH, McCreary AC. Serotonergic Approaches in Parkinson's Disease: Translational Perspectives, an Update. ACS Chem Neurosci 2017; 8:973-986. [PMID: 28460160 DOI: 10.1021/acschemneuro.6b00440] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Parkinson's disease (PD) has long been seen as a disorder caused by degeneration of the dopaminergic system, leading to the classic motor manifestations of the disease. However, there is now overwhelming evidence that PD is more than a disease merely caused by dopamine depletion. It is well-known that a myriad of other neurotransmitters are affected by the disease process. One such neurotransmitter is serotonin (5-HT). 5-HT has been shown to play a role in several motor and nonmotor manifestations of PD, including tremor, cognition, depression and psychosis. 5-HT also seems to play a critical role in L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia. A breadth of preclinical studies and clinical trials have been conducted that aimed at modulating the 5-HT system in order to alleviate depression, cognitive deficits, psychosis, and dyskinesia. In this Review, we summarize recent advances in the 5-HT field in PD, but with a translational emphasis. We start by presenting a novel nonhuman primate model of PD that presents with dual dopamine and 5-HT lesions. We then present preclinical and clinical data that introduce new concepts, such as the use of biased and partial agonists, as well as molecules recently introduced to the field of PD, such as eltoprazine, pimavanserin, nelotanserin, and SYN-120, to enhance therapeutic benefit while minimizing adverse events, notably on parkinsonian disability.
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Affiliation(s)
- Philippe Huot
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montreal, QC H2X 0A9, Canada
- Department
of Pharmacology, Université de Montréal, Montreal, QC H3T 1J4, Canada
- Unité
des Troubles du Mouvement André Barbeau, Centre Hospitalier de l’Université de Montréal, Montreal, QC H2L 4M1, Canada
- Division
of Neurology, Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada
| | - Véronique Sgambato-Faure
- Institute of Cognitive
Neuroscience Marc Jeannerod, UMR 5229 CNRS, 69 675 Cedex Bron, France
- University Lyon 1, 69100 Villeurbanne, France
| | - Susan H. Fox
- Movement
Disorder Clinic, Toronto Western Hospital, University of Toronto, Toronto, ON M5T2S8, Canada
| | - Andrew C. McCreary
- Janssen Vaccines & Prevention B.V., Archimedesweg 4, 2333 CN Leiden, The Netherlands
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Ffytche DH, Creese B, Politis M, Chaudhuri KR, Weintraub D, Ballard C, Aarsland D. The psychosis spectrum in Parkinson disease. Nat Rev Neurol 2017; 13:81-95. [PMID: 28106066 PMCID: PMC5656278 DOI: 10.1038/nrneurol.2016.200] [Citation(s) in RCA: 224] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
In 2007, the clinical and research profile of illusions, hallucinations, delusions and related symptoms in Parkinson disease (PD) was raised with the publication of a consensus definition of PD psychosis. Symptoms that were previously deemed benign and clinically insignificant were incorporated into a continuum of severity, leading to the rapid expansion of literature focusing on clinical aspects, mechanisms and treatment. Here, we review this literature and the evolving view of PD psychosis. Key topics include the prospective risk of dementia in individuals with PD psychosis, and the causal and modifying effects of PD medication. We discuss recent developments, including recognition of an increase in the prevalence of psychosis with disease duration, addition of new visual symptoms to the psychosis continuum, and identification of frontal executive, visual perceptual and memory dysfunction at different disease stages. In addition, we highlight novel risk factors - for example, autonomic dysfunction - that have emerged from prospective studies, structural MRI evidence of frontal, parietal, occipital and hippocampal involvement, and approval of pimavanserin for the treatment of PD psychosis. The accumulating evidence raises novel questions and directions for future research to explore the clinical management and biomarker potential of PD psychosis.
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Affiliation(s)
- Dominic H Ffytche
- KCL-PARCOG group, Institute of Psychiatry, Psychology &Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, UK
- Department of Old Age Psychiatry, Institute of Psychiatry, Psychology &Neuroscience, King's College London, UK. De Crespigny Park, London SE5 8AF, UK
| | - Byron Creese
- KCL-PARCOG group, Institute of Psychiatry, Psychology &Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, UK
- University of Exeter Medical School, University of Exeter, EX1 2LU, UK
| | - Marios Politis
- KCL-PARCOG group, Institute of Psychiatry, Psychology &Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, UK
- Neurodegeneration Imaging Group, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology &Neuroscience, King's College London, 125 Coldharbour Lane, London SE5 9NU, UK
| | - K Ray Chaudhuri
- KCL-PARCOG group, Institute of Psychiatry, Psychology &Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, UK
- Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, National Parkinson Foundation Centre of Excellence, King's College London/Kings College Hospital, 5 Cutcombe Road, London SE5 9RT, UK
| | - Daniel Weintraub
- KCL-PARCOG group, Institute of Psychiatry, Psychology &Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, UK
- Departments of Psychiatry and Neurology, Perelman School of Medicine at the University of Pennsylvania 3615 Chestnut Street, #330, Philadelphia, Pennsylvania 19104, USA
- Parkinson's Disease and Mental Illness Research, Education and Clinical Centres (PADRECC and MIRECC), Philadelphia Veterans Affairs Medical Centre 3900 Woodland Avenue, Philadelphia, Pennsylvania 19104, USA
| | - Clive Ballard
- KCL-PARCOG group, Institute of Psychiatry, Psychology &Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, UK
- University of Exeter Medical School, University of Exeter, EX1 2LU, UK
| | - Dag Aarsland
- KCL-PARCOG group, Institute of Psychiatry, Psychology &Neuroscience, King's College London, De Crespigny Park, London SE5 8AF, UK
- Department of Old Age Psychiatry, Institute of Psychiatry, Psychology &Neuroscience, King's College London, UK. De Crespigny Park, London SE5 8AF, UK
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11
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Qamar MA, Sauerbier A, Politis M, Carr H, Loehrer PA, Chaudhuri KR. Presynaptic dopaminergic terminal imaging and non-motor symptoms assessment of Parkinson's disease: evidence for dopaminergic basis? NPJ Parkinsons Dis 2017; 3:5. [PMID: 28649605 PMCID: PMC5445592 DOI: 10.1038/s41531-016-0006-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 11/04/2016] [Accepted: 11/25/2016] [Indexed: 02/08/2023] Open
Abstract
Parkinson's disease (PD) is now considered to be a multisystemic disorder consequent on multineuropeptide dysfunction including dopaminergic, serotonergic, cholinergic, and noradrenergic systems. This multipeptide dysfunction leads to expression of a range of non-motor symptoms now known to be integral to the concept of PD and preceding the diagnosis of motor PD. Some non-motor symptoms in PD may have a dopaminergic basis and in this review, we investigate the evidence for this based on imaging techniques using dopamine-based radioligands. To discuss non-motor symptoms we follow the classification as outlined by the validated PD non-motor symptoms scale.
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Affiliation(s)
- MA Qamar
- National Parkinson’s Foundation International Center of Excellence, King’s College London and King’s College Hospital NHS Foundation Trust, London, UK
| | - A Sauerbier
- National Parkinson’s Foundation International Center of Excellence, King’s College London and King’s College Hospital NHS Foundation Trust, London, UK
| | - M Politis
- Neurodegeneration Imaging Group, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London, London, UK
| | - H Carr
- National Parkinson’s Foundation International Center of Excellence, King’s College London and King’s College Hospital NHS Foundation Trust, London, UK
| | - P A Loehrer
- National Parkinson’s Foundation International Center of Excellence, King’s College London and King’s College Hospital NHS Foundation Trust, London, UK
- Department of Neurology, University Hospital Cologne, Cologne, Germany
| | - K Ray Chaudhuri
- National Parkinson’s Foundation International Center of Excellence, King’s College London and King’s College Hospital NHS Foundation Trust, London, UK
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12
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ffytche DH, Aarsland D. Psychosis in Parkinson's Disease. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2017; 133:585-622. [DOI: 10.1016/bs.irn.2017.04.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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13
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Xing Y, Tang Y, Zhao L, Wang Q, Qin W, Ji X, Zhang J, Jia J. Associations between plasma ceramides and cognitive and neuropsychiatric manifestations in Parkinson's disease dementia. J Neurol Sci 2016; 370:82-87. [PMID: 27772793 DOI: 10.1016/j.jns.2016.09.028] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 08/16/2016] [Accepted: 09/16/2016] [Indexed: 12/24/2022]
Abstract
BACKGROUND The abnormal metabolism of ceramides may account for the pathogenesis of Parkinson's disease dementia (PDD). However, the effect of ceramides on cognitive domain impairments and neuropsychiatric symptoms of PDD remains unknown. METHODS A total of 38 PDD, 40 PD with no cognitive impairment (PD-NC) and 40 normal controls were included. A series of cognitive tests and the Neuropsychiatric Inventory (NPI) were used to assess cognitive domains and neuropsychiatric symptoms. A non-fasting blood sample was obtained from each subject. Plasma ceramide levels were tested by HPLC-MS/MS analysis. RESULTS C14:0 and C24:1 levels were significantly higher in PDD than in PD-NC and normal controls. Verbal memory was negatively correlated with C14:0 and C24:1. After controlling for confounding factors, C22:0, C20:0 and C18:0 were significantly associated with hallucinations, anxiety and sleep behavior disturbances, respectively. CONCLUSION In PDD, the increase in ceramide levels was correlated with decreased memory function and associated with higher odds of multiple neuropsychiatric symptoms.
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Affiliation(s)
- Yi Xing
- Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, China
| | - Yi Tang
- Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, China
| | - Lina Zhao
- Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, China
| | - Qi Wang
- Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, China
| | - Wei Qin
- Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, China
| | - Xiaojuan Ji
- Department of Cadre Health Care, Beijing Jishuitan Hospital, Beijing, China
| | - Jinlan Zhang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
| | - Jianping Jia
- Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, China; Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
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14
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Imaging Dopamine and Serotonin Systems on MPTP Monkeys: A Longitudinal PET Investigation of Compensatory Mechanisms. J Neurosci 2016; 36:1577-89. [PMID: 26843639 DOI: 10.1523/jneurosci.2010-15.2016] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
UNLABELLED It is now widely accepted that compensatory mechanisms are involved during the early phase of Parkinson's disease (PD) to delay the expression of motor symptoms. However, the neurochemical mechanisms underlying this presymptomatic period are still unclear. Here, we measured in vivo longitudinal changes of both the dopaminergic and serotonergic systems in seven asymptomatic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated monkeys (when motor symptoms are less apparent) using PET. We used the progressively MPTP-intoxicated monkey model that expresses recovery from motor symptoms to study the changes in dopamine synthesis ([(18)F]DOPA), dopamine D2/D3 receptors ([(11)C]raclopride), and serotonin transporter (11)C-N,N-dimethyl-2-(-2-amino-4-cyanophenylthio) benzylamine ([(11)C]DASB) and serotonin 1A receptor ([(18)F]MPPF) levels between four different states (baseline, early symptomatic, full symptomatic and recovered). During the early symptomatic state, we observed increases of [(18)F]DOPA uptake in the anterior putamen, [(11)C]raclopride binding in the posterior striatum, and 2'-methoxyphenyl-(N-2'-pyridinyl)-p-[(18)F]fluoro-benzamidoethylpiperazine [(18)F]MPPF uptake in the orbitofrontal cortex and dorsal ACC. After recovery from motor symptoms, the results mainly showed decreased [(11)C]raclopride binding in the anterior striatum and limbic ACC. In addition, our findings supported the importance of pallidal dopaminergic neurotransmission in both the early compensatory mechanisms and the functional recovery mechanisms, with reduced aromatic L-amino acid decarboxylase (AAAD) activity closely related to the appearance or perseveration of motor symptoms. In parallel, this study provides preliminary evidence of the role of the serotonergic system in compensatory mechanisms. Nonetheless, future studies are needed to determine whether there are changes in SERT availability in the early symptomatic state and if [(18)F]MPPF PET imaging might be a promising biomarker of early degenerative changes in PD. SIGNIFICANCE STATEMENT The present research provides evidence of the potential of combining a multitracer PET imaging technique and a longitudinal protocol applied on a progressively 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-intoxicated monkey model to further elucidate the nature of the compensatory mechanisms involved in the preclinical period of Parkinson's disease (PD). In particular, by investigating the dopaminergic and serotonergic changes both presynaptically and postsynaptically at four different motor states (baseline, early symptomatic, full symptomatic, and recovered), this study has allowed us to identify putative biomarkers for future therapeutic interventions to prevent and/or delay disease expression. For example, our findings suggest that the external pallidum could be a new target for cell-based therapies to reduce PD symptoms.
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Deficits in Striatal Dopamine and Hippocampal Serotonin Following Induction of Anxiety/Depressive-Like Behaviors by Bisphenol A. ARCHIVES OF NEUROSCIENCE 2014. [DOI: 10.5812/archneurosci.18555] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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16
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Miguelez C, Morera-Herreras T, Torrecilla M, Ruiz-Ortega JA, Ugedo L. Interaction between the 5-HT system and the basal ganglia: functional implication and therapeutic perspective in Parkinson's disease. Front Neural Circuits 2014; 8:21. [PMID: 24672433 PMCID: PMC3955837 DOI: 10.3389/fncir.2014.00021] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Accepted: 02/27/2014] [Indexed: 01/15/2023] Open
Abstract
The neurotransmitter serotonin (5-HT) has a multifaceted function in the modulation of information processing through the activation of multiple receptor families, including G-protein-coupled receptor subtypes (5-HT1, 5-HT2, 5-HT4-7) and ligand-gated ion channels (5-HT3). The largest population of serotonergic neurons is located in the midbrain, specifically in the raphe nuclei. Although the medial and dorsal raphe nucleus (DRN) share common projecting areas, in the basal ganglia (BG) nuclei serotonergic innervations come mainly from the DRN. The BG are a highly organized network of subcortical nuclei composed of the striatum (caudate and putamen), subthalamic nucleus (STN), internal and external globus pallidus (or entopeduncular nucleus in rodents, GPi/EP and GPe) and substantia nigra (pars compacta, SNc, and pars reticulata, SNr). The BG are part of the cortico-BG-thalamic circuits, which play a role in many functions like motor control, emotion, and cognition and are critically involved in diseases such as Parkinson's disease (PD). This review provides an overview of serotonergic modulation of the BG at the functional level and a discussion of how this interaction may be relevant to treating PD and the motor complications induced by chronic treatment with L-DOPA.
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Affiliation(s)
- Cristina Miguelez
- Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU Leioa, Spain ; Department of Pharmacology, Faculty of Pharmacy, University of the Basque Country UPV/EHU Vitoria-Gasteiz, Spain
| | - Teresa Morera-Herreras
- Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU Leioa, Spain
| | - Maria Torrecilla
- Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU Leioa, Spain
| | - Jose A Ruiz-Ortega
- Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU Leioa, Spain ; Department of Pharmacology, Faculty of Pharmacy, University of the Basque Country UPV/EHU Vitoria-Gasteiz, Spain
| | - Luisa Ugedo
- Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country UPV/EHU Leioa, Spain
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Goldman JG, Stebbins GT, Dinh V, Bernard B, Merkitch D, deToledo-Morrell L, Goetz CG. Visuoperceptive region atrophy independent of cognitive status in patients with Parkinson's disease with hallucinations. ACTA ACUST UNITED AC 2014; 137:849-59. [PMID: 24480486 DOI: 10.1093/brain/awt360] [Citation(s) in RCA: 115] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Visual hallucinations are frequent, disabling complications of advanced Parkinson's disease, but their neuroanatomical basis is incompletely understood. Previous structural brain magnetic resonance imaging studies suggest volume loss in the mesial temporal lobe and limbic regions in subjects with Parkinson's disease with visual hallucinations, relative to those without visual hallucinations. However, these studies have not always controlled for the presence of cognitive impairment or dementia, which are common co-morbidities of hallucinations in Parkinson's disease and whose neuroanatomical substrates may involve mesial temporal lobe and limbic regions. Therefore, we used structural magnetic resonance imaging to examine grey matter atrophy patterns associated with visual hallucinations, comparing Parkinson's disease hallucinators to Parkinson's disease non-hallucinators of comparable cognitive function. We studied 50 subjects with Parkinson's disease: 25 classified as current and chronic visual hallucinators and 25 as non-hallucinators, who were matched for cognitive status (demented or non-demented) and age (± 3 years). Subjects underwent (i) clinical evaluations; and (ii) brain MRI scans analysed using whole-brain voxel-based morphometry techniques. Clinically, the Parkinson's disease hallucinators did not differ in their cognitive classification or performance in any of the five assessed cognitive domains, compared with the non-hallucinators. The Parkinson's disease groups also did not differ significantly in age, motor severity, medication use or duration of disease. On imaging analyses, the hallucinators, all of whom experienced visual hallucinations, exhibited grey matter atrophy with significant voxel-wise differences in the cuneus, lingual and fusiform gyri, middle occipital lobe, inferior parietal lobule, and also cingulate, paracentral, and precentral gyri, compared with the non-hallucinators. Grey matter atrophy in the hallucinators occurred predominantly in brain regions responsible for processing visuoperceptual information including the ventral 'what' and dorsal 'where' pathways, which are important in object and facial recognition and identification of spatial locations of objects, respectively. Furthermore, the structural brain changes seen on magnetic resonance imaging occurred independently of cognitive function and age. Our findings suggest that when hallucinators and non-hallucinators are similar in their cognitive performance, the neural networks involving visuoperceptual pathways, rather than the mesial temporal lobe regions, distinctively contribute to the pathophysiology of visual hallucinations and may explain their predominantly visual nature in Parkinson's disease. Identification of distinct structural MRI differences associated with hallucinations in Parkinson's disease may permit earlier detection of at-risk patients and ultimately, development of therapies specifically targeting hallucinations and visuoperceptive functions.
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Affiliation(s)
- Jennifer G Goldman
- 1 Rush University Medical Center, Department of Neurological Sciences, Chicago, IL, USA
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Nevalainen N, Af Bjerkén S, Gerhardt GA, Strömberg I. Serotonergic nerve fibers in L-DOPA-derived dopamine release and dyskinesia. Neuroscience 2013; 260:73-86. [PMID: 24361918 DOI: 10.1016/j.neuroscience.2013.12.029] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Revised: 12/04/2013] [Accepted: 12/11/2013] [Indexed: 02/02/2023]
Abstract
The 5-HT (5-hydroxytryptamine) system has been assigned a key role in the development of 3,4-dihydroxyphenyl-l-alanine (l-DOPA)-induced dyskinesia, mainly due to 5-HT neuronal ability to decarboxylate l-DOPA into dopamine. Nevertheless, knowledge of l-DOPA-induced events that could lead to development of dyskinesias are limited and therefore the present work has evaluated (i) the role of the 5-HT system in l-DOPA-derived dopamine synthesis when dopamine neurons are present, (ii) l-DOPA-induced effects on striatal dopamine release and clearance, and on 5-HT nerve fiber density, and (iii) the behavioral outcome of altered 5-HT transmission in dyskinetic rats. Chronoamperometric recordings demonstrated attenuated striatal l-DOPA-derived dopamine release (∼30%) upon removal of 5-HT nerve fibers in intact animals. Interestingly, four weeks of daily l-DOPA treatment yielded similar-sized dopamine peak amplitudes in intact animals as found after a 5-HT-lesion. Moreover, chronic l-DOPA exposure attenuated striatal 5-HT nerve fiber density in the absence of dopamine nerve terminals. Furthermore, fluoxetine-induced altered 5-HT transmission blocked dyskinetic behavior via action on 5-HT1A receptors. Taken together, the results indicate a central role for the 5-HT system in l-DOPA-derived dopamine synthesis and in dyskinesia, and therefore potential l-DOPA-induced deterioration of 5-HT function might reduce l-DOPA efficacy as well as promote the upcoming of motor side effects.
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Affiliation(s)
- N Nevalainen
- Integrative Medical Biology, Umeå University, 901 87 Umeå, Sweden
| | - S Af Bjerkén
- Integrative Medical Biology, Umeå University, 901 87 Umeå, Sweden
| | - G A Gerhardt
- Department of Anatomy, Neurobiology, and Neurology, University of Kentucky Medical Center, Lexington, KY, USA
| | - I Strömberg
- Integrative Medical Biology, Umeå University, 901 87 Umeå, Sweden.
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19
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The serotonergic system in motor and non-motor manifestations of Parkinson’s disease. Exp Brain Res 2013; 230:463-76. [DOI: 10.1007/s00221-013-3621-2] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Accepted: 06/10/2013] [Indexed: 12/16/2022]
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20
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Dupre KB, Ostock CY, George JA, Eskow Jaunarajs KL, Hueston CM, Bishop C. Effects of 5-HT1A receptor stimulation on D1 receptor agonist-induced striatonigral activity and dyskinesia in hemiparkinsonian rats. ACS Chem Neurosci 2013; 4:747-60. [PMID: 23496922 DOI: 10.1021/cn300234z] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Accumulating evidence supports the value of 5-HT1A receptor (5-HT1AR) agonists for dyskinesias that arise with long-term L-DOPA therapy in Parkinson's disease (PD). Yet, how 5-HT1AR stimulation directly influences the dyskinetogenic D1 receptor (D1R)-expressing striatonigral pathway remains largely unknown. To directly examine this, one cohort of hemiparkinsonian rats received systemic injections of Vehicle + Vehicle, Vehicle + the D1R agonist SKF81297 (0.8 mg/kg), or the 5-HT1AR agonist ±8-OH-DPAT (1.0 mg/kg) + SKF81297. Rats were examined for changes in abnormal involuntary movements (AIMs), rotations, striatal preprodynorphin (PPD), and glutamic acid decarboxylase (GAD; 65 and 67) mRNA via RT-PCR. In the second experiment, hemiparkinsonian rats received intrastriatal pretreatments of Vehicle (aCSF), ±8-OH-DPAT (7.5 mM), or ±8-OH-DPAT + the 5-HT1AR antagonist WAY100635 (4.6 mM), followed by systemic Vehicle or SKF81297 after which AIMs, rotations, and extracellular striatal glutamate and nigral GABA efflux were measured by in vivo microdialysis. Results revealed D1R agonist-induced AIMs were reduced by systemic and intrastriatal 5-HT1AR stimulation while rotations were enhanced. Although ±8-OH-DPAT did not modify D1R agonist-induced increases in striatal PPD mRNA, the D1R/5-HT1AR agonist combination enhanced GAD65 and GAD67 mRNA. When applied locally, ±8-OH-DPAT alone diminished striatal glutamate levels while the agonist combination increased nigral GABA efflux. Thus, presynaptic 5-HT1AR stimulation may attenuate striatal glutamate levels, resulting in diminished D1R-mediated dyskinetic behaviors, but maintain or enhance striatal postsynaptic factors ultimately increasing nigral GABA levels and rotational activity. The current findings offer a novel mechanistic explanation for previous results concerning 5-HT1AR agonists for the treatment of dyskinesia.
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Affiliation(s)
- Kristin B. Dupre
- Behavioral Neuroscience
Program, Department of Psychology, Binghamton University, Binghamton, New York 13902-6000, United States
| | - Corinne Y. Ostock
- Behavioral Neuroscience
Program, Department of Psychology, Binghamton University, Binghamton, New York 13902-6000, United States
| | - Jessica A. George
- Behavioral Neuroscience
Program, Department of Psychology, Binghamton University, Binghamton, New York 13902-6000, United States
| | - Karen L. Eskow Jaunarajs
- Behavioral Neuroscience
Program, Department of Psychology, Binghamton University, Binghamton, New York 13902-6000, United States
| | - Cara M. Hueston
- Behavioral Neuroscience
Program, Department of Psychology, Binghamton University, Binghamton, New York 13902-6000, United States
| | - Christopher Bishop
- Behavioral Neuroscience
Program, Department of Psychology, Binghamton University, Binghamton, New York 13902-6000, United States
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Riahi G, Morissette M, Lévesque D, Rouillard C, Samadi P, Parent M, Di Paolo T. Effect of chronic l-DOPA treatment on 5-HT(1A) receptors in parkinsonian monkey brain. Neurochem Int 2012; 61:1160-71. [PMID: 22940695 DOI: 10.1016/j.neuint.2012.08.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2012] [Revised: 08/09/2012] [Accepted: 08/15/2012] [Indexed: 12/16/2022]
Abstract
After chronic use of l-3,4-dihydroxyphenylalanine (l-DOPA), most Parkinson's disease (PD) patients suffer from its side effects, especially motor complications called l-DOPA-induced dyskinesia (LID). 5-HT(1A) agonists were tested to treat LID but many were reported to worsen parkinsonism. In this study, we evaluated changes in concentration of serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) and of 5-HT(1A) receptors in control monkeys, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys, dyskinetic MPTP monkeys treated chronically with l-DOPA, low dyskinetic MPTP monkeys treated with l-DOPA and drugs of various pharmacological activities: Ro 61-8048 (an inhibitor of kynurenine hydroxylase) or docosahexaenoic acid (DHA) and dyskinetic MPTP monkeys treated with l-DOPA+naltrexone (an opioid receptor antagonist). Striatal serotonin concentrations were reduced in MPTP monkeys compared to controls. Higher striatal 5-HIAA/serotonin concentration ratios in l-DOPA-treated monkeys compared to untreated monkeys suggest an intense activity of serotonin axon terminals but this value was similar in dyskinetic and nondyskinetic animals treated with or without adjunct treatment with l-DOPA. As measured by autoradiography with [(3)H]8-hydroxy-2-(di-n-propyl) aminotetralin (8-OH-DPAT), a decrease of 5-HT(1A) receptor specific binding was observed in the posterior/dorsal region of the anterior cingulate gyrus and posterior/ventral area of the superior frontal gyrus of MPTP monkeys compared to controls. An increase of 5-HT(1A) receptor specific binding was observed in the hippocampus of MPTP monkeys treated with l-DOPA regardless to their adjunct treatment. Cortical 5-HT(1A) receptor specific binding was increased in the l-DOPA-treated MPTP monkeys alone or with DHA or naltrexone and this increase was prevented in low dyskinetic MPTP monkeys treated with l-DOPA and Ro 61-8048. These results highlight the importance of 5-HT(1A) receptor alterations in treatment of PD with l-DOPA.
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Affiliation(s)
- Golnasim Riahi
- Faculty of Pharmacy, Université Laval, Quebec City, Canada
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