The serotonin system: a potential target for anti-dyskinetic treatments and biomarker discovery

Rylander, Daniella

doi:10.1016/s1353-8020(11)70039-6

Cited by 15 publications

(13 citation statements)

References 20 publications

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“…11). Thus, multiple striatal systems may be involved in the regulation of LIDs (Blandini and Armentero, 2012; Carta and Bezard, 2011; Duty, 2012; Huot et al, 2011; Huot et al, 2013; Rylander, 2012). In addition, accumulating evidence indicates a role for other brain regions.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

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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“…Indeed, long-term changes in gene expression, intracellular signaling pathways, neuronal plasticity, and morphology have all been linked to the expression of LIDs (Santini et al, 2009;Cenci and Konradi, 2010;Feyder et al, 2011;Huot et al, 2011;Rangel-Barajas et al, 2011;Zhang et al, 2013b). Moreover, these changes may occur via numerous neurotransmitter systems, such as the dopaminergic, glutamatergic, serotonergic, and others, which are all implicated in the development and maintenance of LIDs (Carta and Bezard, 2011;Huot et al, 2011;Blandini and Armentero, 2012;Duty, 2012;Rylander, 2012;Huot et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

The α7 Nicotinic Receptor Agonist ABT-107 Decreases l-Dopa–Induced Dyskinesias in Parkinsonian Monkeys

Zhang¹,

McGregor²,

Decker³

et al. 2014

J Pharmacol Exp Ther

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Previous studies in Parkinsonian rats and monkeys have shown that b2-selective nicotinic acetylcholine receptor (nAChR) agonists reduce L-Dopa-induced dyskinesias (LIDs), a serious complication of L-Dopa therapy for Parkinson's disease. Since rodent studies also suggested an involvement of a7 nAChRs in LIDs, we tested the effect of the potent, selective a7 agonist . MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned monkeys were gavaged with L-Dopa/carbidopa (10 and 2.5 mg/kg, respectively) twice daily, which resulted in stable LIDs. A dose-response study (0.03-1.0 mg/kg) showed that oral ABT-107 decreased LIDs by 40-60%. LIDs returned to control levels only after a 6-week ABT-107 washout, suggesting that long-term molecular changes were involved. Subsequent readministration of ABT-107 decreased LIDs by 50-60%, indicating that tolerance did not develop. ABT-107 had no effect on Parkinsonism or cognitive performance. We next tested ABT-107 together with the b2 agonist ABT-894 [(3-(5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo [3.2.0]heptane], previously shown to reduce LIDs in Parkinsonian monkeys. In one study, the monkeys were first given oral ABT-894 (0.01 mg/kg), which maximally decreased LIDs by 50-60%; they were then also treated with 0.1 mg/kg ABT-107, a dose that maximally reduced LIDs. The effect of combined treatment on LIDs was similar to that with either drug alone. Comparable results were observed in a group of monkeys first treated with ABT-107 and then also given ABT-894. Thus, a7 and b2 nAChR-selective drugs may function via a final common mechanism to reduce LIDs. The present results suggest that drugs targeting either a7 or b2 nAChRs may be useful as antidyskinetic agents in Parkinson's disease.

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“…Drugs targeting numerous neurotransmitter systems have been shown to attenuate LIDs in animal models of Parkinson’s disease including those interacting at the dopaminergic, serotonergic, glutamatergic, opioid, GABAergic and other systems (Blandini & Armentero, 2012; Brotchie & Jenner, 2011; Cenci, 2007; Duty, 2012; Fox, Chuang, & Brotchie, 2009; Gasparini, Di Paolo, & Gomez-Mancilla, 2013; Huot, et al, 2013; Iravani, et al, 2012; Quik, Mallela, Ly, & Zhang, 2013; Rylander, 2012; Sgambato-Faure & Cenci, 2012). In addition, more recent studies indicate that alterations in nicotinic cholinergic mechanisms modulate LIDs.…”

Section: Role For Nicotine and Nachr Agonists In Reducing L-dopa-imentioning

confidence: 99%

Role for the nicotinic cholinergic system in movement disorders; therapeutic implications

Quik¹,

Zhang²,

Perez³

et al. 2014

Pharmacology & Therapeutics

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A large body of evidence using experimental animal models shows that the nicotinic cholinergic system is involved in the control of movement under physiological conditions. This work raised the question whether dysregulation of this system may contribute to motor dysfunction and whether drugs targeting nicotinic acetylcholine receptors (nAChRs) may be of therapeutic benefit in movement disorders. Accumulating preclinical studies now show that drugs acting at nAChRs improve drug-induced dyskinesias. The general nAChR agonist nicotine, as well as several nAChR agonists (varenicline, ABT-089 and ABT-894) reduce L-dopa-induced abnormal involuntary movements or dyskinesias up to 60% in parkinsonian nonhuman primates and rodents. These dyskinesias are potentially debilitating abnormal involuntary movements that arise as a complication of L-dopa therapy for Parkinson’s disease. In addition, nicotine and varenicline decrease antipsychotic-induced abnormal involuntary movements in rodent models of tardive dyskinesia. Antipsychotic-induced dyskinesias frequently arise as a side effect of chronic drug treatment for schizophrenia, psychosis and other psychiatric disorders. Preclinical and clinical studies also show that the nAChR agonist varenicline improves balance and coordination in various ataxias. Lastly, nicotine has been reported to attenuate the dyskinetic symptoms of Tourette’s disorder. Several nAChR subtypes appear to be involved in these beneficial effects of nicotine and nAChR drugs including α4β2*, α6β2* and α7 nAChRs (the asterisk indicates the possible presence of other subunits in the receptor). Overall, the above findings, coupled with nicotine’s neuroprotective effects, suggest that nAChR drugs have potential for future drug development for movement disorders.

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The serotonin system: a potential target for anti-dyskinetic treatments and biomarker discovery

Cited by 15 publications

References 20 publications

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

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

The α7 Nicotinic Receptor Agonist ABT-107 Decreases l-Dopa–Induced Dyskinesias in Parkinsonian Monkeys

Role for the nicotinic cholinergic system in movement disorders; therapeutic implications

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