Chronic dopaminergic stimulation in Parkinson’s disease: from dyskinesias to impulse control disorders. Lancet Neurol

Wellcome Trust Centre for Neuroimaging, Institute of Neurology, University College London, London, UK.
The Lancet Neurology (Impact Factor: 21.82). 12/2009; 8(12):1140-9. DOI: 10.1016/S1474-4422(09)70287-X
Source: PubMed

ABSTRACT Dopamine is an essential neurotransmitter for many brain functions, and its dysfunction has been implicated in both neurological and psychiatric disorders. Parkinson's disease is an archetypal disorder of dopamine dysfunction characterised by motor, cognitive, behavioural, and autonomic symptoms. While effective for motor symptoms, dopamine replacement therapy is associated not only with motor side-effects, such as levodopa-induced dyskinesia, but also behavioural side-effects such as impulse control disorders (eg, pathological gambling and shopping, binge eating, and hypersexuality), punding (ie, abnormal repetitive non-goal oriented behaviours), and compulsive medication use. We review clinical features, overlapping molecular mechanisms, and a specific cognitive mechanism of habit learning that might underlie these behaviours. We integrate these mechanisms with the emerging view of the basal ganglia as a distributive system involved in the selection and facilitation of movements, acts, and emotions.

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Available from: Pierre-Olivier Fernagut, Aug 18, 2015
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    • "In many cases, pharmacological therapy is unable to provide satisfactory symptom control as the disease progresses and patients on long term medication may develop disabling side effects [1]. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an evidence based treatment in advanced stages of PD as it has been shown to improve motor fluctuations, dyskinesia and quality of life better than medication [2]. Furthermore STN-DBS allows for a reduction in medication [3] which is particularly important for patients suffering from side effects of medication such as impulse control disorders or psychosis. "
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    ABSTRACT: Deep brain stimulation of subthalamic nucleus (STN-DBS) for Parkinson's disease allows for a reduction in medication dosage. Changes in total levodopa equivalent daily dose (LEDD) have been frequently reported, there is little information about changes within the drug classes. We retrospectively assessed the changes in antiparkinsonian drugs dosages in 150 patients from one center who had preoperative and postoperative evaluations at 6 months and 3 years. Two long term subgroups with postoperative follow-up till the 5th-6th year (n = 58) and 10th year (n = 15) were included. The major modifications in medication dosage occurred during the initial postoperative period. LEDD was reduced by 53.4% compared to baseline at 6 months and 47.9% at 3 years. Fifty six percent and 41.3% of the patients were on monotherapy, 9.3% on no medication at 6 months and 6.7% at 3 years post surgery. Patients on levodopa, or dopamine agonists showed similar reductions. At the 3rd year the oldest group of patients showed a significant decrease in dopamine agonists. The number of patients treated with amantadine was significantly reduced; however the number of patients treated with antidepressants was significantly increased over the first 3 years. Annual medication costs per patient were decreased after the DBS-STN implantation by 61.3% at 6 months and 55.4% at 3 years. STN-DBS allows for a reduction in the dosage of medication and the costs are similarly reduced. In this cohort different medication groups were reduced to a similar extent. Patients' demographic factors did not play a major role in the selection of treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Parkinsonism & Related Disorders 03/2015; 21(6). DOI:10.1016/j.parkreldis.2015.03.003 · 4.13 Impact Factor
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    • "The rise in prefrontal DA levels observed along with increased dyskinesia severity might thus be involved in LID expression by promoting unwanted behaviors or by causing irrepressible actions through corticostriatal pathways (Graybiel et al. 2000). Considering that dyskinesia are also triggered or enhanced by stress and emotional situations (Voon et al. 2009), modifications in amygdala and hippocampal DA might participate in LID expression. Altogether, altered integration and action selection/planning might contribute to LID. "
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    ABSTRACT: Beyond dopamine (DA) loss, Parkinson's disease is associated with many other monoamine alterations. While some monoaminergic systems benefit from l-3,4-dihydroxyphenylalanine (l-Dopa) treatment, others seem to be further altered, contributing to dyskinesia and nonmotor symptoms. Surprisingly, the different contributions of parkinsonism and l-Dopa treatment on monoaminergic changes remain largely unknown. Here, both the consequences of vehicle or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure and the subsequent effects of acute or chronic l-Dopa treatment were evaluated in macaques. Monoamine levels were measured in the putamen, the motor and prefrontal cortices, the hippocampus, and the amygdala using postmortem high-pressure liquid chromatography. In normal monkeys, l-Dopa treatment increased DA in the prefrontal cortex and hippocampus, but decreased serotonin levels in motor domains. Chronic l-Dopa treatment elevated monoamine levels in the prefrontal cortex, hippocampus, and amygdala in both normal and MPTP-treated monkeys. A substantial increase in DA levels in these regions, paralleled by a decrease in serotonin concentrations were related with dyskinesia severity, demonstrating that major changes in monoamine release also occur in nonmotor regions. Such monoaminergic dysregulation in limbic domains may also directly contribute to the expression of motor complications, such as dyskinesia, by impairing integrative processes upstream from motor execution.
    Cerebral Cortex 04/2014; 25(9). DOI:10.1093/cercor/bhu076 · 8.67 Impact Factor
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    • "Experiments conducted in rats have shown that several manipulations , including overtraining on a particular schedule of reinforcement, can result in a habitual pattern of behaviour [81] [82], and the same finding has been reported in humans [87]. This property of learned actions could be relevant for disorders such as ICDs and addiction, where previously reinforced behaviour is sustained, irrespective of current negative consequences [41]. Differential neural substrates for goal directed and habitual action have been extensively demonstrated [88] [89] [90] [91] [92] [93] [94] [95]. "
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    ABSTRACT: Non-motor symptoms contribute significantly to Parkinson's disease (PD) related disability. Impulse control disorders (ICDs) have been recently added to the behavioural spectrum of PD-related non-motor symptoms. Such behaviours are characterized by an inappropriate drive to conduct repetitive behaviours that are usually socially inadequate or result in harmful consequences. Parkinson disease impulse control disorders (PD-ICDs) have raised significant interest in the scientific and medical community, not only because of their incapacitating nature, but also because they may represent a valid model of ICDs beyond PD and a means to study the physiology of drive, impulse control and compulsive actions in the normal brain. In this review, we discuss some unresolved issues regarding PD-ICDs, including the association with psychiatric co-morbidities such as obsessive-compulsive disorder and with dopamine related side effects, such as hallucinations and dyskinesias; the relationship with executive cognitive dysfunction; and the neural underpinnings of ICDs in PD. We also discuss the contribution of neuroscience studies based on animal-models towards a mechanistic explanation of the development of PD-ICDs, specifically regarding corticostriatal control of goal directed and habitual actions.
    Behavioural neurology 12/2012; 27(4). DOI:10.3233/BEN-129019 · 1.64 Impact Factor
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