Enhanced histamine H2 excitation of striatal cholinergic interneurons in l-DOPA-induced dyskinesia

Lim, Sean Austin O.; Xia, Rong; Ding, Yunmin; Won, Lisa; Ray, William J.; Hitchcock, Stephen A.; McGehee, Daniel S.; Kang, Un Jung

doi:10.1016/j.nbd.2015.01.003

Cited by 39 publications

(26 citation statements)

References 60 publications

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“…Muscarinic cholinergic receptor involvement in LID is less clear, with cholinergic antagonists at M4 receptors possibly reducing dystonia but exacerbating chorea. Histamine H 2 receptors located within the striatum may reduce LID via modulation of acetylcholine …”

Section: Pathophysiologymentioning

confidence: 99%

Levodopa‐induced dyskinesia in Parkinson disease: Current and evolving concepts

Espay

Morgante

Merola

et al. 2018

Annals of Neurology

249

204

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Levodopa-induced dyskinesia is a common complication in Parkinson disease. Pathogenic mechanisms include phasic stimulation of dopamine receptors, nonphysiological levodopa-to-dopamine conversion in serotonergic neurons, hyperactivity of corticostriatal glutamatergic transmission, and overstimulation of nicotinic acetylcholine receptors on dopamine-releasing axons. Delay in initiating levodopa is no longer recommended, as dyskinesia development is a function of disease duration rather than cumulative levodopa exposure. We review current and in-development treatments for peak-dose dyskinesia but suggest that improvements in levodopa delivery alone may reduce its future prevalence. ANN NEUROL 2018;84:797-811 D yskinesia, often referred to as L-dopa-induced dyskinesia (LID) to recognize L-dopa as the major contributor, is a motor complication arising in patients with Parkinson disease (PD) on chronic L-dopa treatment, largely in a dose-dependent fashion-except when given as an infusion, such as in L-dopa/carbidopa intestinal gel. 1 LID is phenomenologically recognized as chorea/choreoathetoid movements appearing initially on the more affected body side. LID occurs in 40% of patients after 4 years on L-dopa treatment, with risk especially high in younger patients treated with higher doses of L-dopa. 2 This review focuses on aspects of phenomenology, pathophysiology, and therapeutics that have undergone revisions or updates in recent years, emphasizing those of most relevance for modern clinical care and future research. We highlight the under-recognized diphasic dyskinesia, which is often mischaracterized as a peak-dose phenomenon and therefore mismanaged. We review evidence that corrects the misinterpretation of prior clinical trial data surmising LID as a function of duration of Ldopa exposure rather than duration of disease, justifying the inappropriate but still lingering recommendation to postpone L-dopa treatment as long as possible to "delay" the appearance of LID. 3 We also review the latest pathophysiologic concepts at the molecular, synaptic, and network levels, to provide the rationale for currently available as well as emerging treatments. Peak-Dose versus Diphasic DyskinesiaPeak-Dose Dyskinesia. Chorea that may be generalized or affect the more affected side or upper body often occurs during the therapeutic window of a L-dopa dose cycle View this article online at wileyonlinelibrary.com.

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Section: Pathophysiologymentioning

confidence: 99%

Levodopa‐induced dyskinesia in Parkinson disease: Current and evolving concepts

Espay

Morgante

Merola

et al. 2018

Annals of Neurology

249

204

View full text Add to dashboard Cite

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“…The only drug available for the treatment of LIDs is amantadine, which has variable efficacy, response durability and tolerability (Crosby et al, 2003; Luginger et al, 2000; Rodnitzky and Narayanan, 2014; Thomas et al, 2004). Numerous studies over the last three decades show that alterations in the dopaminergic, serotonergic, glutamatergic, GABAergic, noradrenergic, histaminergic and opioid systems are involved in LIDs; however, identification of clinical therapies targeting these systems has proved elusive (Blandini and Armentero, 2012; Cenci, 2007; Gasparini et al, 2013; Huot et al, 2013; Iravani et al, 2012; Lim et al, 2015; Rylander, 2012). …”

Section: Introductionmentioning

confidence: 99%

Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias

Bordia

Perez

Heiss

et al. 2016

Neurobiology of Disease

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L-dopa-induced dyskinesias (LIDs) are a serious complication of L-dopa therapy for Parkinson's disease. Emerging evidence indicates that the nicotinic cholinergic system plays a role in LIDs, although the pathways and mechanisms are poorly understood. Here we used optogenetics to investigate the role of striatal cholinergic interneurons in LIDs. Mice expressing cre-recombinase under the control of the choline acetyltransferase promoter (ChAT-Cre) were lesioned by unilateral injection of 6-hydroxydopamine. AAV5-ChR2-eYFP or AAV5-control-eYFP was injected into the dorsolateral striatum, and optical fibers implanted. After stable virus expression, mice were treated with L-dopa. They were then subjected to various stimulation protocols for 2 h and LIDs rated. Continuous stimulation with a short duration optical pulse (1-5 ms) enhanced LIDs. This effect was blocked by the general muscarinic acetylcholine receptor (mAChR) antagonist atropine indicating it was mAChR-mediated. By contrast, continuous stimulation with a longer duration optical pulse (20 ms to 1 s) reduced LIDs to a similar extent as nicotine treatment (~50%). The general nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine blocked the decline in LIDs with longer optical pulses showing it was nAChR-mediated. None of the stimulation regimens altered LIDs in control-eYFP mice. Lesion-induced motor impairment was not affected by optical stimulation indicating that cholinergic transmission selectively regulates LIDs. Longer pulse stimulation increased the number of c-Fos expressing ChAT neurons, suggesting that changes in this immediate early gene may be involved. These results demonstrate that striatal cholinergic interneurons play a critical role in LIDs and support the idea that nicotine treatment reduces LIDs via nAChR desensitization.

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“…This is supported by the observation that, in a mouse model of PD, short-pulse optogenetic stimulation of Chl exacerbates the dyskinetic response to l -DOPA (Bordia et al 2016). Conversely, in the same PD model, LID is reduced by interventions that counteract Chl hyper-excitability by antagonizing excitatory histamine H2 receptors, whose activity is pathologically enhanced in the Chl of dyskinetic mice (Lim et al 2015). …”

Section: Extracellular Signal-regulated Kinases 1/2: Central Players mentioning

confidence: 99%

Signal transduction in l-DOPA-induced dyskinesia: from receptor sensitization to abnormal gene expression

Spigolon

Fisone

2018

J Neural Transm

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A large number of signaling abnormalities have been implicated in the emergence and expression of l-DOPA-induced dyskinesia (LID). The primary cause for many of these changes is the development of sensitization at dopamine receptors located on striatal projection neurons (SPN). This initial priming, which is particularly evident at the level of dopamine D1 receptors (D1R), can be viewed as a homeostatic response to dopamine depletion and is further exacerbated by chronic administration of l-DOPA, through a variety of mechanisms affecting various components of the G-protein-coupled receptor machinery. Sensitization of dopamine receptors in combination with pulsatile administration of l-DOPA leads to intermittent and coordinated hyperactivation of signal transduction cascades, ultimately resulting in long-term modifications of gene expression and protein synthesis. A detailed mapping of these pathological changes and of their involvement in LID has been produced during the last decade. According to this emerging picture, activation of sensitized D1R results in the stimulation of cAMP-dependent protein kinase and of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa. This, in turn, activates the extracellular signal-regulated kinases 1 and 2 (ERK), leading to chromatin remodeling and aberrant gene transcription. Dysregulated ERK results also in the stimulation of the mammalian target of rapamycin complex 1, which promotes protein synthesis. Enhanced levels of multiple effector targets, including several transcription factors have been implicated in LID and associated changes in synaptic plasticity and morphology. This article provides an overview of the intracellular modifications occurring in SPN and associated with LID.

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Enhanced histamine H2 excitation of striatal cholinergic interneurons in l-DOPA-induced dyskinesia

Cited by 39 publications

References 60 publications

Levodopa‐induced dyskinesia in Parkinson disease: Current and evolving concepts

Levodopa‐induced dyskinesia in Parkinson disease: Current and evolving concepts

Optogenetic activation of striatal cholinergic interneurons regulates L-dopa-induced dyskinesias

Signal transduction in l-DOPA-induced dyskinesia: from receptor sensitization to abnormal gene expression

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