Selective Inactivation of Striatal FosB/ΔFosB-Expressing Neurons Alleviates L-DOPA–Induced Dyskinesia
Michel EngelnMatthieu F. BastideEstelle ToulméBenjamin DehayMathieu BourdenxÉvelyne DoudnikoffQin LiChristian E. GrossÉric Boué‐GrabotAntonio PisaniErwan BézardPierre‐Olivier Fernagut
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FOSB
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Background/Aim. Levodopa, the precursor of dopamine, is a substitute therapy for Parkinson''s disease. Long-term application of levodopa causes fluctuation in motor response and the occurrence of involuntary movements or dyskinesia. The aim of this study was to assess the risk factors for dyskinesia in Parkinson?s disease (PD) patients undergoing treatment with levodopa. Methods. We included 177 consecutive outpatients with PD, who had been undergoing treatment for at least six months. A semi-structured interview was used to collect demo-graphic and clinical data as well as a number of clinical scales. Results. Patients with dyskinesia (n = 90) were younger at dis-ease onset and had longer disease duration. They had higher Unified Parkinson''s Disease Rating Scale (UPDRS) scores and more frequently had other motor complications, such as wearing-off and freezing of gait, as well as non-motor ones, such as psychosis. They took higher levodopa doses and levodopa equivalent doses and were on levodopa therapy for a longer period of time. Multivariate analysis yielded that in-dependent risk factors for dyskinesia were: disease duration of longer than 10 years
Movement Disorders
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Chronic pulsatile levodopa therapy for Parkinson's disease (PD) leads to the development of motor fluctuations and dyskinesia. We studied the prevalence and predictors of levodopa-induced dyskinesia among multiethnic Malaysian patients with PD.This is a cross-sectional study involving 95 patients with PD on uninterrupted levodopa therapy for at least 6 months. The instrument used was the UPDRS questionnaires. The predictors of dyskinesia were determined using multivariate logistic regression analysis.The mean age was 65.6 ± 8.5 years. The mean onset age was 58.5 ± 9.8 years. The median disease duration was 6 (7) years. Dyskinesia was present in 44% (n = 42) with median levodopa therapy of 3 years. There were 64.3% Chinese, 31% Malays, and 3.7% Indians and other ethnic groups. Eighty-one percent of patients with dyskinesia had clinical fluctuations. Patients with dyskinesia had lower onset age ( p < 0.001), longer duration of levodopa therapy ( p < 0.001), longer disease duration ( p < 0.001), higher total daily levodopa dose ( p < 0.001), and higher total UPDRS scores ( p = 0.005) than patients without dyskinesia. The three significant predictors of dyskinesia were duration of levodopa therapy, onset age, and total daily levodopa dose.The prevalence of levodopa-induced dyskinesia in our patients was 44%. The most significant predictors were duration of levodopa therapy, total daily levodopa dose, and onset age.
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Abstract The duration of the antiparkinsonian action of levodopa was studied in 48 patients with various response patterns to the oral administration of the dopamine precursor. Deterioration in motor scores after abrupt cessation of a steady‐state intravenous levodopa infusion occurred at two successive rates: an initial rapid phase followed by a terminal slower phase. Efficacy half‐time Decemberreased and initial efficacy Decemberay slope increased with progression of levodopa response groups from never treated to stable responders, and then to fluctuating responders of the wearing‐off type and finally of the on‐off type. Efficacy half‐time exceeded plasma levodopa half‐life in the 2 nonfluctuating groups, approximated it in those patients with wearing‐off responses, and was significantly shorter in patients with fluctuations of the on‐off type. The half‐times for the Decemberline in antiparkinsonian efficacy and dyskinesia severity differed significantly, suggesting different pharmacological mechanisms. Motor fluctuation severity correlated best with initial efficacy Decemberay slope, and both were best predicted by parkinsonian symptom severity. The dyskinesia Decemberay rate correlated most closely with levodopa dose. These results support the view that progressive dopamine neuron degeneration reduces the brain's ability to buffer shifts in levodopa availability attending its periodic oral administration; the clinical result is wearing‐off phenomenon. The on‐off phenomenon as well as dyskinesia apparently reflects additional secondary changes related to levodopa therapy and occurring postsynaptically.
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Purpose/aim: Retrocollis can substantially disturb the daily living of individuals with Parkinson's disease (PD). Clinician often encounter the difficulty in managing the retrocollis. Materials and Methods: We describe a patient with PD who presented with choreic dyskinesia and levodopa-responsive retrocollis. Results: The patient had dyskinesia and the off periods, and received levodopa (700 mg, 14 times/day). The patient received levodopa-carbidopa intestinal gel (LCIG) treatment. After several months, the patient complained of difficulty in swallowing and speech due to severe retrocollis. Thirty minutes following a fast levodopa infusion of LCIG, the retrocollis improved. As a result, a frontal view was obtained, and her talking abilities showed improvement. Conclusions: Severe retrocollis can be superimposed on choreic dyskinesia, and it was likely to increase during the off periods. Duodenal levodopa infusion may reduce the severity of retrocollis.
Pramipexole
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ΔFosB plays a critical role in drug-induced long-term changes in the brain. In the current study, we evaluated locomotor activity in male and female rats treated with saline or cocaine for 2 weeks and quantitatively mapped ΔFosB expression in the dorsal striatum and nucleus accumbens of each animal by using an anti-FosB antibody that recognizes ΔFosB isoforms preferentially. Behavioral analysis showed that while there was little difference between males and females that sensitized to cocaine, nonsensitizing rats showed a large sex difference. Nonsensitizing males showed low behavioral activation in response to cocaine on the first day of treatment, and their activity remained low. In contrast, nonsensitizing females showed high activation on the first day of treatment and their activity remained high. Western blot and immunohistochemical analyses indicated that basal levels of ΔFosB were higher in the nucleus accumbens than the dorsal striatum, but that the effect of cocaine on ΔFosB was greater in the dorsal striatum. Immunostaining showed that the effect of cocaine in both the dorsal striatum and nucleus accumbens was primarily to increase the intensity of ΔFosB immunoreactivity in individual neurons, rather than to increase the number of cells that express ΔFosB. Detailed mapping of ΔFosB-labeled nuclei showed that basal ΔFosB levels were highest in the medial portion of the dorsal striatum and dorsomedial accumbens, particularly adjacent to the lateral ventricle, whereas the cocaine-induced increase in ΔFosB was most pronounced in the lateral dorsal striatum, where basal ΔFosB expression was lowest. Sex differences in ΔFosB expression were small and independent of cocaine treatment. We discuss implications of the sex difference in locomotor activation and regionally-specific ΔFosB induction by cocaine.
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Levodopa-induced dyskinesia (LID) is a major impediment to the successful therapy of Parkinson's disease. The development of LID is facilitated by dopaminergic denervation but may not require denervation. Repeated levodopa dosing is necessary to induce dyskinesia, implying the development of sensitization to levodopa. There is inconclusive evidence on whether repeated dosing lowers the threshold (shifts the levodopa-dyskinesia response curve to the left), increases the severity of dyskinesia (increases the maximum effect that is initially zero) or induces more complex changes in the dose-response curve. Once a patient develops LID, the severity of LID is not dose responsive, but the duration of dyskinesia is. Clinically, it is very difficult to separate the antiparkinsonian and dyskinetic effects of levodopa. Whether this separation is possible with more selective agonists with antiparkinsonian effects that are equipotent to levodopa is unknown. The fact that selective stimulation of the pallidum does not separate antiparkinsonian and dyskinetic actions implies that they are closely related anatomically and physiologically.
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