Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013421 (dystonia)
 8,418 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Animal data indicate that serotonin (5-HT) is a major neurotransmitter involved in the control of numerous central nervous system functions including mood, aggression, pain, anxiety, sleep, memory, eating behavior, addictive behavior, temperature control, endocrine regulation, and motor behavior. Moreover, there is evidence that abnormalities of 5-HT functions are related to the pathophysiology of diverse neurological conditions including Parkinson's disease, tardive dyskinesia, akathisia, dystonia, Huntington's disease, familial tremor, restless legs syndrome, myoclonus, Gilles de la Tourette's syndrome, multiple sclerosis, sleep disorders, and dementia. The psychiatric disorders of schizophrenia, mania, depression, aggressive and self-injurious behavior, obsessive compulsive disorder, seasonal affective disorder, substance abuse, hypersexuality, anxiety disorders, bulimia, childhood hyperactivity, and behavioral disorders in geriatric patients have been linked to impaired central 5-HT functions. Tryptophan, the natural amino acid precursor in 5-HT biosynthesis, increases 5-HT synthesis in the brain and, therefore, may stimulate 5-HT release and function. Since it is a natural constituent of the diet, tryptophan should have low toxicity and produce few side effects. Based on these advantages, dietary tryptophan supplementation has been used in the management of neuropsychiatric disorders with variable success. This review summarizes current clinical use of tryptophan supplementation in neuropsychiatric disorders.
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PMID:L-tryptophan in neuropsychiatric disorders: a review. 130 30

The genetically dystonic (dt) rat is an animal model of dystonia that displays sustained abnormal movements that include: torticollis, clasping of the hindlimbs, rigidity of the limbs, and contortions of the trunk. Since serotonin (5-HT) has been shown to be involved in some animal models of movement disorders, the functional responsiveness of the 5-HT system in dt rats and phenotypical normal littermates was examined by administering 5-HT agonists selective for different receptor subtypes and observing behavioral responses associated with the activation of specific 5-HT receptor subtypes. The dt rats were 6-fold more sensitive to the ability of the 5-HT1A agonist 8-OH-2-(di-n-propylamino)tetralin (8-OH-DPAT) to produce the 5-HT behavioral syndrome. The dt rats demonstrated a diminished head-shaking response following administration of the 5-HT2 agonist 1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB). However, the dt rats also displayed significantly fewer head shakes following mechanical stimulation of the aural pinnae. The inability of the dt rats to demonstrate head-shaking behavior following stimulation of 5-HT2 receptors is probably due to the dt rat's difficulty in producing the motor responses involved in this behavioral response and do not reflect alterations in 5-HT2 receptor sensitivity. These results suggest that the 5-HT system, particularly 5-HT1A receptors, may have an integral role in the abnormal movements displayed by the genetically dystonic rat and movement disorders in general.
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PMID:Altered behavioral responses mediated by serotonin receptors in the genetically dystonic (dt) rat. 201 8

Neuroleptic drug-induced acute extrapyramidal syndromes (EPS) are the major reasons why patients discontinue their antipsychotic medicines. Serotonin S2 antagonists prevent catalepsy in rodents but the effects in nonhuman primates have received only minimal study and deserve further evaluation as potential "non-neuroleptic neuroleptics" (antipsychotic effects free of acute EPS). Twenty Cebus monkeys (22 to 28 yrs. old) were tested with compounds that ranged from high to very low D2/S2 ratios. These were haloperidol, clopenthixol, tefludazine, and setoperone, all tested in the dosage range of .01 to .25 mg/kg and compared with saline i.m. once weekly in a random schedule. Dystonia was scored on four different symptoms by an experienced rater blind to drug dosage. All four active compounds produced clinically indistinguishable, dose related dystonia with very similar dose thresholds. In contrast to rodent studies these nonhuman primate investigations with drugs of widely differing D2/S2 antagonism ratios produced clinically similar EPS. Thus adding an S2 antagonism component to neuroleptics appears not to provide a unique approach to neuroleptic therapy which will be free of acute EPS.
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PMID:Serotonergic aspects of acute extrapyramidal syndromes in nonhuman primates. 251 34

In rodents, serotonin (5-HT) antagonists counteract behavioral and biochemical effects of neuroleptic drugs. Therefore, we have studied the effect of different 5-HT drugs and one anticholinergic drug in acute dystonia in five cebus monkeys chronically treated with haloperidol. Acute dystonia induced by subcutaneous injections of haloperidol was slightly reduced by the 5-HT antagonist methysergide (4.0 mg/kg), while mianserin, ketanserin, and ritanserin (R 55 667; a new selective and potent 5-HT receptor blocker) had no effect. This was contrasted by the marked antidystonic effect of the anticholinergic drug biperiden (0.05-1.0 mg/kg). The 5-HT agonist citalopram, a specific 5-HT uptake inhibitor, had no significant effect. It is concluded that 5-HT antagonists have no useful effect in neuroleptic-induced dystonia.
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PMID:Effects of serotonergic and anticholinergic drugs in haloperidol-induced dystonia in Cebus monkeys. 347 Jan 40

The effects of serotonin (5-hydroxytryptamine; 5-HT) antagonists and 5-HT uptake inhibitors on the behavioral response to amphetamine and haloperidol in monkeys (cercopithecus aethiops) were investigated. Amphetamine increased locomotor activity and reactivity and induced repetitive movements of head, limbs and trunk, but no oral hyperkinesia. Haloperidol induced dystonia and parkinsonism. Pretreatment with the 5-HT antagonists cyproheptadine and mianserin increased amphetamine-induced locomotor activity, reactivity and repetitive movements and decreased haloperidol-induced dystonia and parkinsonism. Conversely the 5-HT uptake inhibitors paroxetine and CGP 6085 A decreased amphetamine-induced repetitive movements and aggravated haloperidol-induced dystonia and parkinsonism. The 5-HT uptake inhibitors produced oral hyperkinesia resembling human tardive dyskinesia, which was intensified by amphetamine and blocked by haloperidol. These findings support the suggestion that 5-HT inhibits dopamine functions and may imply that 5-HT antagonists could have a beneficial effect against acute extrapyramidal side-effects of neuroleptic treatment. 5-HT uptake inhibitors in the monkey may serve as a model for tardive dyskinesia.
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PMID:Behavioral aspects of serotonin-dopamine interaction in the monkey. 408 56

Neuroleptic drug-induced acute extra-pyramidal syndromes are one of the major reasons why patients discontinue their antipsychotic medicines. The typical (e.g., haloperidol) neuroleptic drug produces acute extrapyramidal symptoms in the majority of patients, whereas the atypical (clozapine) neuroleptic produces only minimal motor system side effects. Serotonin S2 antagonists often reduce or prevent catalepsy in rodents, but the limited number of studies in nonhuman primates have produced conflicting results. The hypothesis of a high serotonin S2/dopamine D2 antagonism ratio as a mechanism underlying atypical neuroleptic effects in preventing acute extrapyramidal syndromes deserves further evaluation in nonhuman primate models because extrapyramidal symptoms in monkeys closely resemble those in patients. Cebus monkeys (22-28 years old) were tested with compounds that ranged from low to high S2/D2 antagonism ratios. These were haloperidol, fluphenazine, clopenthixol, melperone, tefludazine, setoperone, risperidone, and clozapine. A saline control was included with a wide dose range of each of these drugs that was tested in a once-weekly, blindly-scored random drug administration schedule. Dystonia was scored on four different symptoms by an experienced rater who was blind to drug dosage. All the compounds, with the exception of clozapine, produced clinically indistinguishable dose-related dystonia. The only difference was the dose at which dystonia appeared. In contrast to rodent studies, these nonhuman primate investigations with drugs, spanning a wide range of S2/D2 antagonism ratios, produced clinically similar extrapyramidal symptoms. Thus, adding an S2 antagonism component to neuroleptics does not appear to provide an explanation for the motor side effect profile of atypical neuroleptics, or a method for designing neuroleptic drugs that will be free of extrapyramidal symptoms.
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PMID:Serotonergic and dopaminergic aspects of neuroleptic-induced extrapyramidal syndromes in nonhuman primates. 783 41

The genetically dystonic hamster is an animal model of idiopathic (torsion) dystonia that displays sustained abnormal movements and postures either spontaneously or in response to mild environmental stimuli. Since dystonic attacks occur in the absence of any lesion which can be defined by standard histopathological techniques in the central nervous system, the presumption is that dystonia in mutant hamsters is due to some biochemical disturbance activity in brain regions involved in motor functions. In the present study we determined the monoamine neurotransmitters dopamine, noradrenaline, adrenaline and serotonin (5-HT) as well as the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) and the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) in 14 brain regions of male and female dystonic hamsters and age-matched non-dystonic controls. All determinations were done at age of maximum susceptibility for induction of dystonic attacks. Since both genders of dystonic hamsters exhibit the same characteristic age-dependent time-course of dystonia, it was assumed that only those biochemical alterations are critically involved in dystonia that occur in both female and male animals. The neurochemical data show that except for a significant decrease of dopamine and HVA in the olfactory bulb, no consistent changes in dopamine metabolism are present across brain regions, including the basal ganglia, of dystonic hamsters. In contrast, marked increases in noradrenaline and 5-HT or 5-HIAA were found in several brain areas of both genders, indicating an enhanced activity of central noradrenergic and serotonergic nuclei in the brainstem. The present results suggest the involvement of noradrenergic and serotonergic neural systems in the pathophysiology of dystonia. Based on these data and recent theoretical suggestions from clinical findings, drugs which reduce noradrenergic and serotonergic neurotransmission may be a useful therapeutic approach to dystonia.
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PMID:Marked regional disturbances in brain metabolism of monoaminergic neurotransmitters in the genetically dystonic hamster. 783 42

Several clinical and experimental findings suggest that abnormal serotonin (5-HT) function may be involved in movement disorders such as dystonia, and it was proposed that selective 5-HT1A receptor antagonists may be of benefit in treating such disorders. In the present study, the novel, highly selective and silent 5-HT1A receptor antagonist (+)-WAY-100135 (N-tert-butyl-3(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylprop ionamide) was tested in an inbred line of Syrian hamsters with generalized dystonia, i.e. a frequent movement disorder in humans. In order to demonstrate that WAY-100135 acts as a 5-HT1A receptor antagonist in the hamster, the drug was shown to antagonize the behavioural syndrome induced by 8-hydroxy-2-(di-n-propylamino)tetralin. When administered at 5-HT1A receptor antagonistic doses in dystonic hamsters, (+)-WAY-100135 dramatically aggravated the dystonic attacks. The data thus suggest that, in contrast to previous theoretical proposals, 5-HT1A receptor antagonists provide no novel therapeutic approach to involuntary movement disorders such as dystonia.
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PMID:The novel selective and silent 5-HT1A receptor antagonist (+)-WAY-100135 aggravates dystonic movements in a mutant hamster model. 802 48

The genetically dystonic (dtsz) hamster is an autosomal recessive mutant that shares several features with paroxysmal dystonia, i.e., a subcategory of inherited idiopathic dystonia in humans. Because the serotonin (5-HT) system has been suggested to be involved in dystonia, we examined the functional responsiveness of the 5-HT system in dystonic hamsters by administering various 5-HT agonists and antagonists selective for different receptor subtypes and observing the effects on dystonic attacks as well as the behavioural responses associated with drug administration. Paradoxically, marked prodystonic effects (i.e., increased severity and/or decreased latency of dystonic attacks) were seen with both the selective 5-HT1A receptor agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) and the selective and "silent" 5-HT1A receptor antagonist, N-tert-butyl-3[4-(2-methoxyphenyl)piperazin-1-yl]-2- phenylpropionamide [(+)-WAY-100135], whereas other 5-HT1A receptor antagonists, i.e., methyl 4[4-(4-[1,1,3-trioxo-2H-1,2-benzoiosothiazol-2-yl]butyl)-1- piperazinyl]1-H-indole-2-carboxylate (SDZ 216-525) and N1-bromoacetyl-N8-3'-(4-indolyloxy)-2'-hydroxypropyl-(Z)-1,8- diamino-p-methane (pindobind-5-HT1A) did not alter dystonia to any comparable extent. Because among these 5-HT1A receptor antagonists, (+)-WAY-100135 is the only drug known to be not only silent at postsynaptic but also presynaptic (somatodendritic) 5-HT1A receptors, the marked prodystonic effect of this drug could relate to increased 5-HT release as a result of the blockade of somatodendritic 5-HT1A receptors. The only 5-HT1A receptor antagonist that exerted antidystonic effects in hamsters was pindolol, which, however, could be related to its beta-adrenoceptor blocking action. The 5-HT1A receptor partial agonist ipsapirone exerted moderate prodystonic activity. Prodystonic activity was also determined for the mixed 5-HT1A/5-HT2 receptor agonist 5-methoxy-N,N-dimethyltryptamine, although this drug was less potent in this regard than 8-OH-DPAT. The 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) exerted prodystonic effects in mutant hamsters, which, however, were also seen after the administration of the 5-HT2 receptor antagonist ritanserin. Collectively, the results of this study demonstrate that dystonia in genetically dystonic hamsters can be affected by pharmacologic manipulation of 5-HT receptors. The data may also indicate that dystonia is not a potential clinical application for selective 5-HT1A or 5-HT2 receptor antagonists.
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PMID:Behavioural response to pharmacologic manipulation of serotonin receptors in the genetically dystonic hamster. 858 1

The autosomal recessive mutation dystonia musculorum (dt(J)/dt(J)) causes degenerative alterations of peripheral and central sensory pathways that lead to ataxia. To investigate possible changes in the central serotonin system of these mice, HPLC measurements of 5-hydroxytryptophan, 5-hydroxy-tryptamine (serotonin; 5-HT), and 5-HT metabolites were obtained from 22 brain regions and the spinal cord of wild type and dt(J)/dt(J) mutant mice. Also, 5-HT transporters were quantified by [(3)H]citalopram autoradiography in 72 brain regions, subregions, and nuclei, and the 5-HT innervation visualized by immunocytochemistry throughout the brain and spinal cord. In all brain regions measured for indoleamine content, there were no significant differences between the two genotypes. In the spinal cord, an increased tissue concentration of 5-HT (+34%), 5-hydroxyindole-3-acetic acid (+33%), 5-hydroxytryptophol (+21%), and 5-hydroxytryptophan (+45%) in dt(J)/dt(J) actually corresponded to the same total amount of each of these indoleamines in the entire spinal cord, when taking into account its reduced size in the mutants. Quantification of the binding to 5-HT transporters showed increases in the medial geniculate nucleus (+14%), medial (+24%) and lateral (+18%) hypothalamus, interpeduncular (+13%), vestibular (+22%), and deep cerebellar nuclei (+37%) of dt(J)/dt mice, and decreases in the ventral tegmental area (-13%), median and linear raphe nuclei (-20%), as well as in the solitary complex (-35%). There were no apparent differences in the distribution of 5-HT-immunostained fibers in these and other regions of brain and in the spinal cord of dt(J)/dt(J) compared to wild type mice. The bulk of these results indicates a relative sparing of the central 5-HT system in the dt(J)/dt(J) mice, even though alterations in 5-HT transporters could justify attempts at improving the sensorimotor dysfunction by administration of serotoninergic agents in these mice.
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PMID:Central serotonin system in Dystonia musculorum mutant mice: biochemical, autoradiographic and immunocytochemical data. 1088 Oct 40


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