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)

Investigations utilizing agonists for 5-HT receptor subtypes have been conducted to determine which 5-HT receptor subtype(s) subserve myoclonus in the guinea pig. Administration of a nonselective 5-HT agonist such as 5-MeODMT (5-HT1A/5-HT2 agonist) induces a dose-dependent behavior characterized by head jerking at low doses (1-2 mg/kg, SC) and full-blown myoclonus (continuous rhythmic whole-body jerking) at higher doses (2.5-5 mg/kg, SC). In contrast, the selective 5-HT1A receptor agonist 8-OH-DPAT and the selective 5-HT2 receptor agonist DOI do not induce myoclonus, and elicit only limited head jerking across an otherwise behaviorally active range of doses (1-5 mg/kg, SC). Importantly, the coadministration of both 8-OH-DPAT and DOI results in the emergence of dose-dependent myoclonic behavior. These data suggest that coactivation of 5-HT1A and 5-HT2 receptors may be required for the induction of myoclonus in the guinea pig.
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PMID:5-HT-dependent myoclonus in guinea pigs: mediation through 5-HT1A-5-HT2 receptor interaction. 845 15

The brainstem is the locus of serotonin (5-HT)-mediated myoclonus in the guinea pig, which is induced by 5-hydroxy-L-tryptophan (L-5-HTP) and indole but not piperazine 5-HT receptor agonists. As an initial step in testing the hypothesis that one 5-HT receptor subtype mediates this effect, we measured seven 5-HT receptor binding sites and the 5-HT uptake site in guinea pig brainstem and compared them to the rat. In guinea pig brainstem, the rank order of binding site density was: 5-HT transporter site >> 5-HT1D > antagonist-labeled 5-HT2 > 5-HT1A, 5-HT1C > 5-HT1E > agonist-labeled 5-HT2 binding site. There were fewer 5-HT1A and 5-HT1C binding sites and 5-HT uptake sites in guinea pig than rat brainstem, more 5-HT1D and antagonist-labeled 5-HT2 sites, but the differences were 2-fold or less. The major species difference was that 5-HT1B sites were virtually undetectable in guinea pig brainstem. Limited competition experiments with related 5-HT receptor subtype-selective agonists and antagonists suggested that the sites in guinea pig brainstem conformed to those described in the rat. 5-HT agonist and antagonist dose-threshold and dose maximum-effect data from guinea pig myoclonus in vivo were compared with receptor affinities at each receptor site in vitro from the literature. No convincing correlation between myoclonus and one particular 5-HT site was found. These data indicate the presence of a full complement of 5-HT receptor binding site subtypes in guinea pig brainstem with some species differences.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Brainstem serotonin receptors in the guinea pig: implications for myoclonus. 847 16

Following 10 min cardiac arrest and resuscitation, male Sprague-Dawley rats developed posthypoxic myoclonus. This phenomenon peaked at 14 days and disappeared by 60 days after cardiac arrest. From previous results, the 5-hydroxytryptamine (5-HT) system was implicated in the pathogenesis of the disease. In the present study, we investigated the involvement of 5-HT1A receptors in posthypoxic myoclonus in rats. Single injections of 5-HT1A agonists, buspirone (5 and 10 mg/kg body wt.) or 8-OH-DPAT (1, 2, and 4 mg/kg), had no effect on either the intensity or time course of the disease. In contrast, multiple injections (twice a day for 7 or more days) of buspirone (10 mg/kg) or 8-OH-DPAT (4 mg/kg) significantly attenuated the myoclonus scores of animals (p < 0.05). The results indicate that chronic stimulation of 5-HT1A receptors in the brain may accelerate endogenous compensatory mechanisms and shorten the time course of the disease.
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PMID:Chronic treatments with 5-HT1A agonists attenuate posthypoxic myoclonus in rats. 854 77

Male Sprague-Dawley rats underwent cardiac arrest and resuscitation, subsequently exhibiting posthypoxic myoclonus. The audiogenic posthypoxic myoclonus in these animals could be attenuated with the following drugs: 5-hydroxytryptophan (5-HTP, serotonin [5-HT] precursor), N-(3-trifluoro-methylphenyl)piperazine hydrochloride (TFMPP, 5-HT1B/1C/2 agonist), (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrobromide (DOI, 5-HT2 agonist), and 1-(m-chlorophenyl)-biguanide hydrochloride (m-CPBG, 5-HT3 agonist). In contrast, the following drugs were ineffective: (+/-)-8-hydroxy-dipropylaminotetralin hydrobromide (8-OH-DPAT, 5-HT1A agonist), buspirone hydrochloride (5-HT1A agonist), 7-trifluoromethyl-4(4-methyl-l-piperazinyl)-pyrrolo[1,2- a]quinoxaline maleate (CGS 12066B, 5-HT1B agonist), ketanserin tartrate (5-HT2 antagonist), methysergide maleate (5-HT2 antagonist), fluoxetine (5-HT uptake blocker), and saline (vehicle). The data suggest that enhancement of serotonergic activity, particularly through 5-HT2 and 5-HT3 receptors, have therapeutic potential for the treatment of posthypoxic myoclonus.
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PMID:Effects of selective serotonergic ligands on posthypoxic audiogenic myoclonus. 855 14

The immediate serotonin (5-HT) precursor, 5-hydroxy-L-tryptophan (L-5-HTP), is an investigational treatment for myoclonic disorders. Its mechanism of action in humans is incompletely understood. We measured the density of subtypes of 5-HT1 and 5-HT2 receptors and the affinity of 5-HT and L-5-HTP in vitro in the human brainstem and cortex, regions associated with subcortical and cortical myoclonus, respectively. In the cortex, the rank order of 5-HT receptor subtype Bmax was 5-HT2A (low-affinity), 5-HT1A, 5-HT uptake sites, 5-HT1D, 5-HT2C, 5-HT1E/F, and 5-HT2A (high-affinity) sites. In the brainstem, the rank order was 5-HT uptake sites, 5-HT1D, 5-HT2C, 5-HT1A, and 5-HT2A(L) sites. Specific binding at 5-HT1E/F and high-affinity 5-HT2A sites was too low for characterization. In competition studies, 5-HT had high affinity for 5-HT1A and 5-HT2C sites in the brainstem and cortex, but L-5-HTP was > 1,000-fold less active. These data support the hypothesis that in humans L-5-HTP stimulates 5-HT receptors in the CNS only after conversion to 5-HT. They also indicate in the human brainstem a prominence of 5-HT1A sites and paucity of 5-HT1D, 5-HT1E/F, and 5-HT2A sites, which has implications for brainstem-mediated myoclonus and response to serotonergic drugs.
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PMID:Human brainstem serotonin receptors: characterization and implications for subcortical myoclonus. 893 89

In guinea pigs, myoclonus can be induced by 5-hydroxytryptamine (5-HT, serotonin) precursors and synthetic 5-HT receptor agonists, yet the receptor subtype specificity of this behavior is not fully delineated. Guinea pigs were pre-treated with carbidopa (50 mg) followed by one of eight 5-HT antagonists: (-)-N-tert-butyl-3-[4-(2-methoxyphenyl) piperazin-1-yl]-2-phenyl propionamide ((-)-WAY 100135) (5-HT1A), N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridyl)-cy clohexancarboxamide (WAY 100635) (5-HT1A), methiothepin mesylate (5-HT1/2), mesulergine hydrochloride (5-HT2A/2C), N[4-methoxy-3-(4-methyl-L-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2 ,4-oxadizol-3-yl) (GR 127935) (5-HT1D), trans-4-[(3Z)3-(2-dimethylaminoethyl)oxyimino-3(2-fluorop hen yl) propen-1-yl]phenol, hemifumarate (SR 46349) (5-HT2), ondansetron hydrochloride (5-HT3), and [1-[2-[methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl-5-fluoro-2-meth oxy-1H-indole-3-carboxylate (GR 125487) (5-HT4). Thirty minutes later, they received 5-hydroxytryptophan (5-HTP) (75 mg/kg, sc) and myoclonic jumping rates were assessed every 10 min for 200 min by a blinded observer. Repeated measures analysis of variance of drug-induced antagonism of 5-HTP-induced myoclonus revealed a significant effect for the 5-HT receptor antagonists methiothepin mesylate, GR127935, and mesulergine hydrochloride compared to placebo, and each of these drugs inhibited 5-HTP-induced myoclonus in a dose-dependent fashion. Based on the receptor profiles of the three effective antagonists, 5-HTP-induced myoclonus is influenced by the 5-HT1/2 receptor systems. The absence of a significant change with any other receptor subtype antagonist suggests that myoclonus is not related to diffuse activation of central serotonergic mechanisms.
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PMID:5-Hydroxytryptophan-induced myoclonus in guinea pigs: mediation through 5-HT1/2 receptor subtypes. 965 Aug 47

The present study examined the role of 5-hydroxytryptamine 5-HT receptor subtypes on 5-hydroxytryptamine- (5-HT-) mediated myoclonus in guinea pigs, evaluating head and whole-body jerking as two distinct behavioural responses. Myoclonus was induced by the 5-HT precursor L-5-hydroxytryptophan (L-5-HTP) and the non-selective 5-HT1A/1B/5-HT2 receptor agonist 5-methoxy-N,N-dimethyl-tryptamine (5-MeODMT). The selective 5-HT1A receptor antagonist WAY100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cycloh exanecarboxamide trihydrochloride) inhibited both head and whole-body jerking. The selective 5-HT1B/1D receptor antagonist GR127935 (N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1 ,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-carboxamide hemifumarate) only inhibited whole-body jerking, which resulted in unmasked head jerking. Co-administration of GR127935 and the selective 5-HT2A receptor antagonist MDL100.151 ((+/-)-alpha-(2,3-dimethoxyphenyl)-1-[-2-(4-fluorphenyl)ethyl]-4-+ ++piperidinmethanol) caused a complete inhibition of whole-body as well as head jerking. MDL100.151 had only limited effect on myoclonic jerking when given alone. The inhibitory effects of the 5-HT receptor antagonists on either L-5-HTP- or 5-MeODMT-induced myoclonus were found to be very similar. These data confirm a role for the 5-HT1A and 5-HT1B/1D receptors and suggest a role for 5-HT2A receptors in mediating myoclonus in guinea pigs. Moreover, the study shows that by considering head and whole-body jerking as two pharmacologically distinct behavioural responses, subtype specific 5-HT1A, 5-HT1B/1D and 5-HT2A receptor antagonists can be distinguished.
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PMID:Head and whole-body jerking in guinea pigs are differentially modulated by 5-HT1A, 5-HT1B/1D and 5-HT2A receptor antagonists. 986 7


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