The novel selective and silent 5-HT1A receptor antagonist (+)-WAY-100135 aggravates dystonic movements in a mutant hamster model

Löscher, Wolfgang; Richter, Angelika

doi:10.1016/0014-2999(94)90103-1

Cited by 6 publications

(2 citation statements)

References 12 publications

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“…Rats depleted of serotoninergic neurons show no abnormality of baseline movement (14). Yet the genetically dystonic rat has diminished motor responses that involve serotoninergic systems and increased sensitivity to 5-HT 1A serotoninergic agonists (15), and the genetically dystonic hamster is dramatically worsened by 5-HT 1A antagonists (16). In humans, the serotonin syndrome is becoming increasingly recognized in patients taking drugs that increase synaptic serotonin or stimulate serotonin receptors (17,18).…”

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confidence: 99%

Selective Decrease in Central Nervous System Serotonin Turnover in Children with Dopa-Nonresponsive Dystonia

Assmann

Köhler

Hoffmann³

et al. 2002

Pediatr Res

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Childhood dystonia that does not respond to treatment with levodopa (dopa-nonresponsive dystonia, DND) has an unclear pathogenesis and is notoriously difficult to treat. To test the hypothesis that there may be abnormalities in serotonin turnover in DND we measured cerebrospinal fluid (CSF) concentrations of homovanillic (HVA) and 5-hydroxyindoleacetic (HIAA) acids, metabolites of dopamine and serotonin, respectively, in 18 children with dystonia not responsive to levodopa. These were combined with a reference population of 85 children with neurologic or metabolic disease known not to affect dopamine or serotonin metabolism. Because of the known natural age-related decrement in HVA and HIAA concentrations, the results were analyzed using multiple regression using age and DND as predictors of CSF HIAA and HVA concentrations. DND was a highly significant predictor of CSF HIAA concentration (p Ͻ 0.001) but not of CSF HVA concentration (p ϭ 0.59). After fitting a regression model, the geometric mean ratio of CSF HIAA in DND compared with the reference range was 0.53 whereas that for CSF HVA was 0.95. We also analyzed CSF HIAA/HVA ratios. After fitting a regression model, we found no dependence on age, and the mean of CSF HIAA/HVA in DND was 0.28 whereas that for the reference range was 0.49 (p Ͻ 0.001). We conclude that a significant number of children with DND have reduced CNS serotonin turnover. Treatment with drugs that increase serotonin concentration in the synaptic cleft should be considered in this group of patients. Childhood dystonias can pragmatically be divided into those that respond to treatment with levodopa and those that do not. Those that do respond to levodopa usually have some parkinsonian features and have been termed parkinsonism-dystonia. Parkinsonism-dystonia syndromes are often caused by deficiency of the neurotransmitter dopamine resulting from inborn errors of the dopamine biosynthesis pathways (1, 2). Dystonia that does not respond to levodopa has a wide variety of causes, and its pathogenesis is poorly understood. Although the study of the acidic metabolites of dopamine and the individual pterin species in human CSF has been fruitful in understanding the mechanisms causing parkinsonism-dystonia in children and young adults (1,(3)(4)(5), it has been disappointing in other movement disorders such as DND. This latter group of patients is also notoriously difficult to treat.Serotonin and dopamine metabolism in the brain are closely linked at both a biochemical and at a physiologic level (6, 7). The basal ganglia of both animals and man have a large serotoninergic projection from the midbrain raphe nuclei (8 -12). However, the function of this in the control of movement is not entirely clear. Impaired CNS serotonin metabolism has been found in adult-onset idiopathic focal dystonias (13). Rats depleted of serotoninergic neurons show no abnormality of baseline movement (14). Yet the genetically dystonic rat has diminished motor responses that involve serotoninergic systems and increased sensitiv...

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confidence: 99%

Selective Decrease in Central Nervous System Serotonin Turnover in Children with Dopa-Nonresponsive Dystonia

Assmann

Köhler

Hoffmann³

et al. 2002

Pediatr Res

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“…A second person who had prepared the solutions, observed the animals for behavioural effects. The side effects were not quantified, but locomotor activity and ataxia were determined according to a score system, as described previously (Löscher and Richter, 1994). Animals which differed in their individual maximum dystonic stage by more than two scores between pre‐drug and post‐drug controls were omitted from evaluation.…”

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confidence: 99%

Antidystonic effects of K_v7 (KCNQ) channel openers in the dt^sz mutant, an animal model of primary paroxysmal dystonia

Richter

Sander

Rundfeldt³

2006

British J Pharmacology

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Background and purpose: Mutations in neuronal K v 7 (KCNQ) potassium channels can cause episodic neurological disorders. Paroxysmal dyskinesias with dystonia are a group of movement disorders which are regarded as ion channelopathies, but the role of K v 7 channels in the pathogenesis and as targets for the treatment have so far not been examined. Experimental approach: In the present study, we therefore examined the effects of the activators of neuronal K v 7.2/7.3 channels retigabine (5, 7.5, 10 mg kg À1 i.p. and 10, 20 mg kg À1 p.o.) and flupirtine (10, 20 mg kg À1 i.p.) and of the channel blocker 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE-991, 3 and 6 mg kg À1 i.p.) in the dt sz mutant hamster, a model of paroxysmal dyskinesia in which dystonic episodes occur in response to stress. Key results: Retigabine (10 mg kg À1 i.p., 20 mg kg À1 p.o.) and flupirtine (20 mg kg À1 i.p.) significantly improved dystonia, while XE-991 caused a significant aggravation in the dt sz mutant. The antidystonic effect of retigabine (10 mg kg À1 i.p.) was counteracted by XE-991 (3 mg kg À1 i.p.). Conclusions and Implications: These data indicate that dysfunctions of neuronal K v 7 channels deserve attention in dyskinesias. Since retigabine and flupirtine are well tolerated in humans, the present finding of pronounced antidystonic efficacy in the dt sz mutant suggests that neuronal K v 7 channel activators are interesting candidates for the treatment of dystonia-associated dyskinesias and probably of other types of dystonias. The established analgesic effects of K v 7 channel openers might contribute to improvement of these disorders which are often accompanied by painful muscle spasms.

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Behavioural response to pharmacologic manipulation of serotonin receptors in the genetically dystonic hamster

Richter

Löscher

1995

Pharmacology Biochemistry and Behavior

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The novel selective and silent 5-HT1A receptor antagonist (+)-WAY-100135 aggravates dystonic movements in a mutant hamster model

Cited by 6 publications

References 12 publications

Selective Decrease in Central Nervous System Serotonin Turnover in Children with Dopa-Nonresponsive Dystonia

Selective Decrease in Central Nervous System Serotonin Turnover in Children with Dopa-Nonresponsive Dystonia

Antidystonic effects of K_v7 (KCNQ) channel openers in the dt^sz mutant, an animal model of primary paroxysmal dystonia

Behavioural response to pharmacologic manipulation of serotonin receptors in the genetically dystonic hamster

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The novel selective and silent 5-HT1A receptor antagonist (+)-WAY-100135 aggravates dystonic movements in a mutant hamster model

Cited by 6 publications

References 12 publications

Selective Decrease in Central Nervous System Serotonin Turnover in Children with Dopa-Nonresponsive Dystonia

Selective Decrease in Central Nervous System Serotonin Turnover in Children with Dopa-Nonresponsive Dystonia

Antidystonic effects of Kv7 (KCNQ) channel openers in the dtsz mutant, an animal model of primary paroxysmal dystonia

Behavioural response to pharmacologic manipulation of serotonin receptors in the genetically dystonic hamster

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Antidystonic effects of K_v7 (KCNQ) channel openers in the dt^sz mutant, an animal model of primary paroxysmal dystonia