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)

Pretreatment with 5-hydroxytryptophan (5-HTP), a precursor of 5-HT, antagonised while pretreatment with p-chlorophenylalanine (PCPA), a 5-HT depletor, potentiated the myoclonus induced by picrotoxin, a GABA antagonist. Pretreatment with aminooxyacetic acid (AOAA), a GABA transaminase inhibitor, antagonised picrotoxin-induced myoclonus. The combined effect of the least protective doses of AOAA and 5-HTP was greater than the sum of their individual inhibitory effects on picrotoxin-induced myoclonus. Further, AOAA failed to inhibit picrotoxin-induced myoclonus in PCPA pretreated rats. These findings suggest that the central 5-HT-ergic system exerts a facilitatory influence on the GABA-ergic system and thus it is involved in the antimyoclonic action of GABA.
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PMID:A functional interaction between GABA and 5-HT in inhibiting picrotoxin-induced myoclonus in rats. 214 69

"Denervation supersensitivity" of serotonin (5-HT) receptors has been proposed to explain the behavioral supersensitivity to 5-hydroxytryptophan (5-HTP) which develops after lesions of indoleamine neurons with 5,7-dihydroxytryptamine (5,7-DHT). To examine the possible role of receptor recognition sites and second messenger activity in supersensitivity, we measured regional 5-HT2 receptor ligand binding and 5-HT-stimulated phosphoinositide turnover in adult rats with 5,7-DHT lesions made by intracisternal injection and their saline-treated controls. In [3H]ketanserin binding studies of fresh brain tissue two weeks after 5,7-DHT injection, there were no significant changes in frontal cortex, brainstem, or spinal cord in Bmax, Kd, or nH of 5-HT2 receptors, 5,7-DHT lesions did not affect basal levels of [3H]inositol phosphate (IP) accumulation but significantly increased 5-HT-stimulated [3H]IP accumulation in the brainstem (+27%) and cortex (+23%). Because brainstem rather than cortex is involved in 5-HTP-evoked myoclonus, increased 5-HT-stimulated phosphoinositide hydrolysis in brainstem following 5,7-DHT lesions in the rat may be relevant to serotonergic behavioral supersensitivity.
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PMID:Regional central serotonin-2 receptor binding and phosphoinositide turnover in rats with 5,7-dihydroxytryptamine lesions. 215 84

Myoclonus is a clinical term meaning a quick involuntary jerk, seen in normal subjects under certain circumstances, including sleep, and in certain disease states. It is important as a symptom that may impair function and as an indicator of neurological dysfunction. Not until patients with myoclonus and major functional disability were reported in the 1960s was attention given to understanding its basis and pharmacotherapy. Reports of myoclonus developing after anoxic brain injury, and its response to treatment with the serotonin precursor 5-hydroxytryptophan (5-HTP), drew special attention. Further experience showed that only a few patients with myoclonus benefit from 5-HTP therapy. Benzodiazepines (BDZs) are often helpful in the treatment of myoclonus. Their beneficial effects decline with chronic administration because of drug tolerance, and the theoretical basis for BDZ responses remains unclear. The relationships between myoclonus, clonus, and epilepsy are discussed, as is the possible contribution of slow signaling transmembrane receptors to synchronization of motoneuron firing, which is suggested as a hallmark of myoclonus. Myoclonus may originate in many CNS sites, but the brain-stem reticular formation is especially relevant to myoclonus. Brain-stem serotonin neurons have special influence on spinal motoneurons, on startle responses, and on myoclonus. Among 5-HT receptors, 5-HT1A receptors are related to some forms of myoclonus, although 5-HT2 receptors are also implicated. GABAA receptors are related to some forms of myoclonus. Blockade of GABAA receptors or GABA synthesis regularly evokes convulsive seizures, but administration of many GABA agonists and some GABA uptake blockers paradoxically may evoke myoclonus. Injection of GABA receptor blockers into some brain areas has anticonvulsant effects. Stimulation of GABAA receptors may therefore promote or antagonize myoclonus depending on which GABA receptors are involved, the state of the system, etc. The role of glycine receptors is well established in some animal models, but has yet to be clearly established for human myoclonus. Opiates may produce myoclonus when given intrathecally or in high dosage. The concept of excitant anesthetics and special function of certain GABA receptors is discussed.
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PMID:Myoclonus: analysis of monoamine, GABA, and other systems. 216 12

We report a 3-year-11-month-old boy who manifested action myoclonus only. Histochemical analysis of the quadriceps muscle revealed subsarcolemmal hyperactivity. The administration of 5-hydroxytryptophan and carbidopa dramatically improved the action myoclonus and reduced an amplitude of giant somatosensory evoked potentials. A nosological relation of this case with "essential myoclonus" and mitochondrial encephalomyopathy was discussed.
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PMID:Improvement of action myoclonus by an administration of 5-hydroxytryptophan and carbidopa in a child with muscular subsarcolemmal hyperactivity. 228 84

A 72-year-old woman suffered a respiratory arrest following intoxication with barbiturates. Her examination 27 months after the anoxic incident revealed involuntary jerks of trunk and limb muscles triggered by willed movements. On a regimen of 1 g L-5-HTP and 100 mg l-alpha-methyldopa hydrazine (carbidopa), action myoclonus disappeared completely. This medication had to be discontinued because of a regressive hysterical reaction. Two months later, she was found unconscious; resuscitation efforts were unsuccessful. Autopsy showed death was caused by choking on food. Coronal slices of the cerebral hemispheres and transverse section of the brainstem and cerebellum revealed no lesion. No evidence of hypoxic damage could be demonstrated in the cerebral cortex, hippocampus, striatum, pallidum, subthalamus, thalamus, or other diencephalic structures. In the caudal half of the midbrain tegmentum, a marked astrocytic reaction of some duration was encountered in the lateral parts of the supratrochlearis nucleus, the lateral subnucleus of the mesencephalic gray, and the immediately adjacent cuneiform and subcuneiform nuclei. In the former nucleus, sites of presumed nerve cell disintegration were found, but the neuronal populations of this nucleus and of the other raphe nuclei were well maintained. The other brainstem structures and the cerebellum were normal. Our neuropathological findings suggest that hypoxic myoclonus (a) does not seem to be explained by demonstrable neuronal loss in motor structures, such as cerebellum, thalamus, or basal ganglia and (b) does not appear to be causally related to a detectable reduction in the serotonin-containing neurons of the brain but rather to a functional derangement of anatomically intact serotonergic pathways originating perhaps from other, as yet unidentified, damaged neuronal structures.
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PMID:Pathological findings in a case of hypoxic myoclonus treated with 5-hydroxytryptophan and a decarboxylase inhibitor. 241 47

Indoleamine-induced myoclonus in guinea pigs is a specific model of brainstem 5-HT function that can be used to characterize the indoleamine systems initiating myoclonus. 5-HT precursors and indole-containing 5-HT agonists induce myoclonus in guinea pigs, but piperazine-containing compounds do not. This selectivity of action correlates with the ability of 5-HT agonists to act at 5-HT-1 receptors. Further evidence for the involvement of a brainstem 5-HT receptor subpopulation in the initiation of myoclonus is shown by the differential ability of 5-HT antagonists to inhibit 5-HTP-induced myoclonus and of 5-HT reuptake blockers to potentiate threshold myoclonus. Distinct tryptamine receptors also may be involved in producing myoclonus, since indoleamine antagonists show differing potencies in inhibiting 5-HTP- and tryptamine-induced myoclonus. Tryptamine-induced myoclonus is, however, dependent on intact presynaptic 5-HT function. Biochemical studies indicate that 5-HT is primarily responsible for 5-HTP-evoked myoclonus, whereas tryptamine predominates in tryptamine-induced myoclonus. Both 5-HT and tryptamine may contribute to myoclonus produced by L-tryptophan. Indoleamine-induced myoclonus in guinea pigs may be valuable in studying the organization of brainstem indoleamine systems that may be involved in some forms of human myoclonus.
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PMID:5-HT-mediated myoclonus in the guinea pig as a model of brainstem 5-HT and tryptamine receptor action. 241 49

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

Clonazepam is a potent anticonvulsant 1,4-benzodiazepine that controls some types of myoclonus. Its primary mode of action is to facilitate GABAergic transmission in the brain by a direct effect on benzodiazepine receptors. GABA receptors lie on the cell bodies of dorsal raphe neurons, and GABA acts to inhibit raphe cell firing, an action potentiated by benzodiazepines. Clonazepam does not alter 5-HT synthesis but decreases 5-HT utilization in brain and blocks the egress of 5-HIAA from the brain. It is not known whether the actions of clonazepam in altering 5-HT function are responsible for its antimyoclonic action, since these are observed only after large doses. Also, the effects of clonazepam are the exact opposite of those predicted from the beneficial effects of 5-HTP in human myoclonic disorders. Finally, why clonazepam, more than other benzodiazepines, is of benefit in the treatment of myoclonus is not clear. This may be due to some pharmacokinetic feature of the drug in conjunction with its potency at benzodiazepine receptors.
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PMID:Mechanism of action of clonazepam in myoclonus in relation to effects on GABA and 5-HT. 241 52

Posthypoxic action myoclonus is usually associated with impaired serotonin (5-HT) neurotransmission but in some patients 5-HT precursors aggravate and 5-HT blockers improve action myoclonus. We studied a 65-year-old man who presented with action myoclonus following a prolonged episode of moderate hypoxia and severe hypercarbia. The myoclonus increased with 5-hydroxytryptophan (5-HTP) 1,200 mg/day plus carbidopa 300 mg/day and sodium salt of valproic acid (SVA) 800 mg/day, and improved with 1 mg of clonazepam (CNZ) in an intravenous bolus. Biochemical analysis of the cerebrospinal fluid (CSF) prior to any drug therapy did not reveal abnormalities in the levels of homovanillic acid (HVA) and methoxyhydroxyphenylglycol (MHPG) but 5-hydroxyindoleacetic acid (5-HIAA) levels were elevated in comparison with controls (33 versus 21 ng/ml). SVA therapy produced a moderate increase and 5-HTP plus carbidopa a threefold elevation of 5-HIAA in CSF and marked aggravation of action myoclonus. Methysergide (3 mg/day) totally suppressed myoclonus and decreased CSF 5-HIAA to undetectable levels. Methysergide also reduced CSF tryptophan to 40% of baseline levels. Discontinuation of methysergide and substitution by placebo was followed by reappearance of myoclonus. A partial and incomplete spontaneous remission of symptoms took place 7 months after the asphyxic episode. Action myoclonus and enhanced 5-HT neurotransmission may be present in patients in which acidosis reverses the effects of hypoxia on 5-HT neurotransmission.
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PMID:Clinical, biochemical, and pharmacological observation in a patient with postasphyxic myoclonus: association to serotonin hyperactivity. 245 56

The capacity of the serotonin (5-HT) precursor 5-HIP to induce the ACTH-responsive myoclonic-convulsive disorder infantile spasms in patients with Down's syndrome has been cited as evidence for altered serotonergic neurotransmission in infantile spasms. Since there is no animal model of infantile spasms, the suitability of behavioral supersensitivity (myoclonus) evoked by 5-HTP in rats with 5,7-dihydroxytryptamine (DHT) lesions as a model was tested by determining the effect of chronic treatment with ACTH (40 IU/kg) on 5-HTP-evoked myoclonus. In rats treated with DHT as adults, ACTH administration did not alter the "serotonergic behaviors," such as myoclonus, induced by 30 mg/kg 5-hydroxytryptophan (5-HTP), but induced a small significant increase in Bmax of neocortical 5-HT2 sites of the DHT group, with no change in rats without lesions. In rats treated with DHT as neonates, there was also no significant difference in behaviors evoked by several doses of 5-HTP. These data suggest that ACTH minimally modifies the effects on 5-HT receptors of DHT lesions, but the intracisternal DHT model is not a suitable model for infantile spasms because chronic ACTH was not antimyoclonic.
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PMID:Chronic ACTH treatment: influence on 5-HT2 receptors and behavioral supersensitivity induced by 5,7-dihydroxytryptamine lesions. 254 29


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