Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027066 (myoclonus)
 4,275 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p,p'-DDT (600 mg/kg) produces myoclonic activity in mice which can be reduced by L-5-hydroxytryptophan (L-5HTP) (200 mg/kg), H75/12 (25 mg/kg), serotonin uptake blockers and two alpha-receptor blockers, phenoxybenzamine (5 mg/kg) and trazodone (5 mg/kg). Decreasing endogenous brain serotonin by pretreatment with p-chlorophenylalanine (400 mg/kg i.p.) blocked the antimyoclonic action of all of these drugs except L-5HTP. Seven other alpha-receptor blockers (phentolamine, tolazoline, yohimbine, azapetine, aceperone, nicergoline and prazosin) potentiated the antimyoclonic activity of a small dose of L-5HTP (50 mg/kg) in this animal model. We postulate that an alpha noradrenergic inhibitory synapse may be located in the neural circuit connecting a serotonergic neuron to the final motor response (p,p'-DDT-induced myoclonus).
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PMID:DDT-induced myoclonus: serotonin and alpha noradrenergic interaction. 3 58

p,p'-DDT (100 to 600 mg per kilogram orally) produced spontaneous and stimulus-sensitive myoclonus in mice and rats. Drugs that enhance brain serotonergic activity reduced p,p'-DDT-induced myoclonus, and serotonin antagonists invariably aggravated this syndrome. p,p'-DDT-treated rats had increased concentrations of 5-hydroxyindoleacetic acid (5-HIAA) in seven regional areas, but serotonin was increased only in the midbrain and cerebellum. We postulate that p,p'-DDT-induced myoclonus may be causally related to blockage of serotonin receptors or inhibition of serotonin release into the synapse, resulting in functional deficiency of this neurotransmiter at the receptor site.
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PMID:p,p'-DDT-induced neurotoxic syndrome: experimental myoclonus. 31 46

Clonazepam (5-(2-chlorophenyl)-1,3-dihydro-7-nitro 2H-1,4 benzodiazepin-2-one) (2 mg/kg) reduced a p,p'-DDT-induced myoclonus in mice by 50%. This antimyoclonic action of clonazepam was counteracted by the serotonin (5-HT) receptor blockers methysergide, metergoline and cinnanserin and potentiated by the 5-HT uptake inhibitors fluoxetine and chlorimipramine. Clonazepam (4 mg/kg) reduced plasma tryptophan by 27%, but had no effect on brain tryptopham, 5-HT, 5-hydroxyindoleacetic acid, 5-HT synthesis and 3H-5-HT receptor binding. Clonazepam (10(-5) M) inhibited brain synaptosomal 3H-5-HT uptake by 23% and increased 3H-5-HT release by 24%. However, 2-8 mg/kg of clonazepam administered intraperitoneally had no effect on 5-HT uptake or release. gamma-Aminobutyric acid (GABA) agonists (muscimol, acetylenic GABA, amino-oxyacetic acid) and the GABA antagonists bicuculline and isoniazid had no effect on p,p'-DDT-induced myoclonus. Furthermore, bicuculline did not counteract the antimyoclonic effect of clonazepam. We suggest that the antimyoclonic action of clonazepam is mediated by enhancement of serotonergic rather than GABAergic neurotransmission.
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PMID:Antimyoclonic action of clonazepam: the role of serotonin. 52 Apr 16

Abnormal glycinergic neurotransmission has been implicated in the pathophysiology of DDT-induced myoclonus. To examine the role of glycine receptors in the DDT model, was measured [3H]strychnine receptor binding in brainstem and spinal cord in the rat after acute administration of DDT. The highest dose of DDT tested significantly increased both Bmax (20%) and Kd (57%) of glycine sites in spinal cord but not brainstem compared to vehicle-treated controls at 4 h. Lower DDT doses, which also induced myoclonus, had no significant effects on [3H]strychnine specific binding. In vitro, 10(-7) DDT did not displace [3H]strychnine binding in naive rat spinal cord, but higher doses could not be studied due to poor solubility of DDT under the assay conditions. These data suggest that only a maximal dose of DDT has significant though mixed effects on parameters of [3H]strychnine binding in spinal cord which are not correlated with the onset of myoclonus.
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PMID:Regional glycine receptor binding in the p,p'-DDT myoclonic rat model. 131 18

p,p'-DDT-induced myoclonus in mice has been proposed as a model of stimulus-sensitive action myoclonus responsive to L-5-HTP and clonazepam treatment. However, we have been unable to confirm the ability of clonazepam to reduce myoclonus induced by p,p'-DDT in the rat. A detailed pharmacological, biochemical, and physiological investigation in the latter species shows p,p'-DDT-induced myoclonus not to resemble stimulus-sensitive action myoclonus occurring in humans. Precursors of 5-HT (L-tryptophan and L-5-HTP) reduced the intensity of myoclonus, but the 5-HT agonists quipazine and Org 6582 did not. 5-HT antagonists (methergoline, methysergide, and cinanserin) did not potentiate myoclonus induced by p,p'-DDT. In contrast, administration of MAOIs (pargyline, nialamide, and tranylcypromine) markedly attenuated the myoclonus. No observable changes in cerebral 5-HT biochemical parameters occurred at the onset of myoclonus, although brain tryptophan and 5-HIAA were increased following periods of prolonged myoclonus. Electrophysiological analysis of p,p'-DDT-induced myoclonus in the rat revealed changes in EEG and EMG activity that were different from those observed in human reticular reflex myoclonus. In conclusion, in contrast to the mouse, myoclonus induced by p,p'-DDT in the rat does not appear to be a suitable model of 5-HT-sensitive action myoclonus in man.
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PMID:p,p'-DDT-induced myoclonus in the rat and its application as an animal model of 5-HT-sensitive action myoclonus. 241 51

Milacemide, a glycine prodrug that is able to enter the brain readily, has been shown to have an antimyoclonic property in the p,p'-DDT-induced myoclonus syndrome. Milacemide increased regional 5-HT and dopamine and decreased 5-HIAA, DOPAC and HVA levels in naive rats. In p,p'-DDT-treated rats, 5-HT levels were unchanged at the time the rats experienced spontaneous myoclonus in all brain regions except in the striatum, where it increased. 5-HIAA levels increased but did not reach significant levels except in the striatum. Dopamine, DOPAC, HVA and norepinephrine were unchanged. When rats were treated concurrently with both p,p'-DDT and milacemide, regional 5-HT levels were increased and NE levels in the brainstem and cerebellum decreased. Depletion of brain serotonin by pretreatment with PCPA or with 5,7-DHT, or blocking 5-HT receptors with different 5-HT antagonists, failed to eliminate the antimyoclonic property of milacemide. This antimyoclonic effect of milacemide may be mediated through other mechanisms besides its ability to increase brain 5-HT levels. Possible mechanisms to be considered are its antiepileptic property, and its ability to increase brain glycine levels. Milacemide may have potential for therapeutic trials in patients with myoclonus.
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PMID:Milacemide increases 5-hydroxytryptamine and dopamine levels in rat brain--possible mechanisms of milacemide antimyoclonic property in the p,p'-DDT-induced myoclonus. 257 9

The acute behavioural consequences of intragastric p,p'-DDT in high doses to mice are stimulus sensitive abrupt muscle jerks (myoclonus). The serotonin (5-HT) precursor 5-hydroxytryptophan (5-HTP) ameliorated in contrast to the natural precursor tryptophan, the neurotoxin-induced myoclonus. The extracerebral decarboxylase inhibitor carbidopa and the selective 5-HT reuptake inhibitor paroxetine both enhanced the antimyoclonic action of 5-HTP. The effect was reversed by the 5-HT receptor blockers cinanserine and methysergide. The data add further evidence to a central serotonergic mechanism involved in p,p'-DDT induced myoclonus.
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PMID:p,p'-DDT-induced myoclonus in mice: the effect of enhanced 5-HT neurotransmission. 298 13

The DDT syndrome in rats consists of tremor, myoclonus, running seizures, hyperthermia, episodic boxing, and excessive grooming. DDT did not change whole-brain glycine levels when the rats had stimulus-sensitive myoclonus, spontaneous myoclonus, or seizures. However, regional analysis showed a decrease in glycine levels in the pons and medulla initially, but they rose again despite worsening of the myoclonus. Glycine given intraventricularly and the glycine prodrug, milacemide, given intraperitoneally suppressed DDT-induced myoclonus. A dose of milacemide that prevented DDT-induced myoclonus caused a significant increase in glycine levels in cortex, septum accumbens, cerebellum, striatum, hippocampus diencephalon, midbrain, pons, and medulla. The increase was most marked in the forebrain structures. There was no change in serine levels in these areas. These data suggest that the glycinergic system may be playing an important role in the manifestation of DDT-induced myoclonus.
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PMID:Glycine involvement in DDT-induced myoclonus. 317 67

Administration of p,p'-DDT to rats produced myoclonus, but unlike previous studies in mice, this was not decreased by administration of clonazepam. Precursors of 5-hydroxytryptamine (5-HT) (L-tryptophan and L-5-HTP) reduced the intensity of myoclonus, but the 5-HT agonists, quipazine and Org 6582 did not. Antagonists of 5-HT (methergoline, methysergide and cinanserin) did not potentiate the myoclonus induced by p,p'-DDT. Drugs altering the function of dopamine and noradrenaline (apomorphine, clonidine or phenoxybenzamine) also had no effect on this myoclonus. Administration of monoamine oxidase inhibitors (MAOIs; pargyline, nialamide and tranylcypromine) markedly attenuated the myoclonus, an effect that could not be attributed to an action on any one monoamine system. No observable changes in cerebral biochemical parameters of 5-HT occurred at the onset of myoclonus, although tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) in brain were increased following periods of prolonged myoclonus. Electrophysiological analysis of the myoclonus in the rat induced by p,p'-DDT revealed changes in EEG and EMG activity which suggested an origin for the myoclonus in the brainstem. Although this was similar to electrophysiological findings in some human patients with post-anoxic action myoclonus, the pharmacological studies suggest that the myoclonus induced by p,p'-DDT in the rat is not a suitable model for screening potential drugs to be used in the treatment of this disorder.
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PMID:Myoclonus in the rat induced by p,p'-DDT and the role of altered monoamine function. 402 63

Since p,p'-DDT-induced myoclonus is ameliorated by serotonin agonists and aggravated by serotonin antagonists, the effect of p,p'-DDT on serotonin metabolism in rat brain was examined. p,p'-DDT (600 mg/kg intragastrically) elevated plasma tryptophan as well as tryptophan and 5-hydroxyindoleacetic acid concentrations in all seven regional areas of the brain assayed. Serotonin levels were elevated only in the midbrain and cerebellum of p,p'-DDT-treated rats. p,p'-DDT increased serotonin turnover in the medulla and midbrain. p,p'-DDT had no effect on the transport of 5-hydroxyindoleacetic acid out of the central nervous system, serotonin uptake and release from nerve terminals, or serotonin receptor binding in the brain. The findings in this study do not support a brain serotonin deficiency hypothesis as the explanation for the response of p,p'-DDT-induced myoclonus to serotonin agonists.
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PMID:p,p'-DDT-induced alterations in brain serotonin metabolism. 617 20


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