Response to Levodopa Treatment in Dopa-Responsive Dystonia

Nutt, John G.; Nygaard, Torbjoern G.

doi:10.1001/archneur.58.6.905

Cited by 44 publications

(24 citation statements)

References 30 publications

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“…Furthermore, in a recent PET study it has been shown that PD patients with dyskinesias have reduced DA transporter expression, supporting the role of presynaptic alterations in the appearance of dyskinesias (27). Finally, clinical observations from DOPA-responsive dystonia show that, despite the fact that these patients have similar levels of striatal DA depletion, dyskinesias do not occur even after long-term (essentially life-long) L-DOPA treatment (28,29). As these patients do not develop DA neurodegeneration, it appears that under conditions when the presynaptic DA compartment is structurally intact, dysplastic changes in the postsynaptic striatal neurons do not lead to development of motor complications.…”

Section: Discussionmentioning

confidence: 92%

Presynaptic dopaminergic compartment determines the susceptibility to L-DOPA–induced dyskinesia in rats

Ulusoy

Şahin

Kirik

2010

Proc. Natl. Acad. Sci. U.S.A.

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Drug-induced dyskinesias in dopamine-denervated animals are known to depend on both pre-and postsynaptic changes of the nigrostriatal circuitry. In lesion models used thus far, changes occur in both of these compartments and, therefore, it has not been possible to dissect the individual contribution of each compartment in the pathophysiology of dyskinesias. Here we silenced the nigrostriatal dopamine neurotransmission without affecting the anatomical integrity of the presynaptic terminals using a short-hairpin RNA-mediated knockdown of tyrosine hydroxylase enzyme (shTH). This treatment resulted in significant reduction (by about 70%) in extracellular dopamine concentration in the striatum as measured by on-line microdialysis. Under these conditions, the animals remained nondyskinetic after chronic L-DOPA treatment, whereas partial intrastriatal 6-hydoxydopamine lesioned rats with comparable reduction in extracellular dopamine levels developed dyskinesias. On the other hand, apomorphine caused moderate to severe dyskinesias in both groups. Importantly, singledose L-DOPA challenge in apomorphine-primed shTH animals failed to activate the already established abnormal postsynaptic responses. Taken together, these data provide direct evidence that the status of the presynaptic, DA releasing compartment is a critical determinant of both the induction and maintenance of L-DOPA-induced dyskinesias.reatment-induced motor complications are a major problem in management of patients suffering from Parkinson's disease (PD) (1). Dyskinesias induced by L-DOPA, in particular, constitute a significant challenge that impacts a higher proportion of the treated patients with treatment duration. Essentially all patients are expected to develop dyskinesias within a decade from onset of treatment (2). The underlying mechanisms of L-DOPA-induced dyskinesias (LIDs) are still not fully understood. Current views suggest that both presynaptic (i.e., production, storage, controlled release, and reuptake of dopamine by nigrostriatal dopaminergic neurons) and postsynaptic (i.e., status of receptors and second messenger signaling pathways in striatal neurons) components are critical in induction and maintenance of dyskinesias (3-5). However, the destruction of the presynaptic dopamine (DA) terminals, typically obtained by administration of a specific neurotoxin in animals, and the plastic changes induced in the postsynaptic striatal neurons occur at the same time. Moreover, synaptic changes secondary to chronic drug treatment further complicate the interpretation of the observations made in studies using animal models of PD (4-6).The aim of this study was to tease apart the contribution of the pre-and postsynaptic compartments in the pathophysiology of LIDs in the parkinsonian brain. The abnormal response of the striatal neurons to DA receptor stimulation following chronic DA depletion could be determined solely by mechanisms intrinsic to the striatal cells or alternatively, the functional activity of the presynaptic compartment could determin...

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Section: Discussionmentioning

confidence: 92%

Presynaptic dopaminergic compartment determines the susceptibility to L-DOPA–induced dyskinesia in rats

Ulusoy

Şahin

Kirik

2010

Proc. Natl. Acad. Sci. U.S.A.

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“…19 Segawa disease is successfully treated with levodopa and the symptoms come back several days after the cessation of levodopa. 20 To exclude the effects of levodopa, we studied our patients 18 to 32 hours after withdrawal from levodopa because these were the longest off period which the patients could tolerate, although a complete washout of levodopa would have required 1 week or more. One article 21 showed abnormal SICI after 1 day cessation of levodopa in Segawa disease.…”

Section: Discussionmentioning

confidence: 99%

Intracortical inhibition of the motor cortex in Segawa disease (DYT5)

Hanajima¹,

Nomura²,

Segawa³

et al. 2007

Neurology

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“…An initial response in a few days can be observed with small doses of levodopa. The presence of chorea and dyskinesias when the levodopa dose is increased in an attempt to obtain a response is indicative of cases that are refractory to therapy 30,35,36 . DRD patients rarely develop motor fluctuations and dyskinesias 36 .…”

Section: Dyt5 Dystoniamentioning

confidence: 99%

The genetics of the dystonias – a review based on the new classification of the dystonias

Camargo

Camargos

Cardoso

et al. 2015

Arq. Neuro-Psiquiatr.

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The definition and classification of the dystonias was recently revisited. In the new 2013 classification, the dystonias are subdivided in terms of their etiology according to whether they are the result of pathological changes or structural damage, have acquired causes or are inherited. As hereditary dystonias are clinically and genetically heterogeneous, we sought to classify them according to the new recently defined criteria. We observed that although the new classification is still the subject of much debate and controversy, it is easy to use in a logical and objective manner with the inherited dystonias. With the discovery of new genes, however, it remains to be seen whether the new classification will continue to be effective.

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Response to Levodopa Treatment in Dopa-Responsive Dystonia

Cited by 44 publications

References 30 publications

Presynaptic dopaminergic compartment determines the susceptibility to L-DOPA–induced dyskinesia in rats

Presynaptic dopaminergic compartment determines the susceptibility to L-DOPA–induced dyskinesia in rats

Intracortical inhibition of the motor cortex in Segawa disease (DYT5)

The genetics of the dystonias – a review based on the new classification of the dystonias

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