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)

Pramipexole (SND 919; 2-amino-4,5,6,7-tetrahydro-6-propyl-amino-benzthiazole- dihydrochloride) was tested for its agonistic activity at pre- and postsynaptic dopamine (DA) receptors. L-Dihydroxyphenylalanine (L-dopa) accumulation in the rat striatum and limbic system and the alpha-methyltyrosine-induced reduction of DA were inhibited. Both effects were fully antagonized by haloperidol but not by the selective DA D1 receptor antagonist SCH 23390. Pramipexole decreased the levels of DA metabolites dose dependently, whereas striatal DA levels remained unchanged. In mice, pramipexole (0.001-1 mg/kg s.c.) reduced exploratory locomotor activity. In rats with unilateral striatal lesions, only weak ipsilateral rotation was produced by pramipexole at the highest dose. However, in rats with unilateral lesions of the medial forebrain bundle, pramipexole potently induced contralateral circling (ED50 0.026 mg/kg s.c.). In the N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model, pramipexole also had potent stimulatory effects. Finally, in haloperidol-sensitized monkeys, the substance did not elicit dyskinesia/dystonia when given alone, but rather inhibited those symptoms which had been induced by haloperidol (ED50 0.116 mg/kg i.m.). It is concluded that pramipexole has therapeutic potential for schizophrenic patients, as a result of its autoreceptor agonistic effects and its weak effects at normosensitive postsynaptic DA receptors. Furthermore, its potent stimulatory effects in DA-depleted animals suggest a possible use in the treatment of Parkinson's disease.
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PMID:Biochemical and pharmacological studies on pramipexole, a potent and selective dopamine D2 receptor agonist. 135 88

The ability of dopamine D1 antagonists to produce acute extrapyramidal syndromes (EPS) in nonhuman primates is unclear. Some studies in monkeys show that D1 antagonists produce acute dystonia, whereas other studies do not report these effects. The central issues that have yielded conflicting results revolve around prior treatment status (neuroleptic-naive versus neuroleptic sensitized) and route of administration (oral versus parenteral). In this study, separate groups of neuroleptic drug-naive cebus monkeys were tested once weekly with intramuscularly administered SCH 23390, a D1 antagonist, or haloperidol, a D2 antagonist, across a dose range of 0.01-0.25 mg/kg, and a saline control. Both active drugs, but not saline, produced clinically identical syndromes of acute dystonia and bradykinesia, though haloperidol induced higher symptom scores over a longer duration. Sedation and locomotor activity were unchanged by SCH 23390, but decreased with haloperidol. Factors regarding acute EPS liability in nonhuman primate models and clinical implications in man are discussed.
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PMID:Dopamine D1 (SCH 23390) and D2 (haloperidol) antagonists in drug-naive monkeys. 153 77

The effects of dopamine D1 and D2 receptor agonists and antagonists were studied in eight Cebus apella monkeys previously treated with haloperidol for two years. SKF 81297 (specific D1 receptor agonist) induced oral hyperkinesia of variable intensity (P less than 0.01): some of the monkeys developed extreme lip smacking, tonque protrusions and licking movements while others developed only slight lip movements. A combined treatment of SKF 81297 with LY 171555 (full D2 receptor agonist) or SCH 23390 (D1 receptor antagonist) inhibited the oral hyperkinesia induced by SKF 81297 (P less than 0.01, P less than 0.02, respectively). Raclopride (D2 receptor antagonist) did not statistically change oral hyperkinesia (P less than 0.2), although five monkeys showed increased oral movements; most of these monkeys had pre-existing hyperkinesia. Treatment with SCH 23390 or raclopride resulted in an identical dystonic/cataleptic syndrome. SKF 81297 inhibited the dystonia induced by SCH 23390, while it did not significantly affect raclopride dystonia. The investigation indicates that oral dyskinesia may be related to an imbalance in D1 receptor and D2 receptor stimulation in favor of D1 receptors. The question now is whether D1 receptor antagonists, which may have antipsychotic potential, will produce tardive dyskinesia after long-term use.
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PMID:The effects of dopamine D1 and D2 receptor agonists and antagonists in monkeys withdrawn from long-term neuroleptic treatment. 198 Aug 91

Administration of the indirect agonist L-dopa, the nonselective direct agonist apomorphine, or the selective D2 agonist (+)-PHNO, reversed parkinsonism and induced locomotor activation in MPTP-treated squirrel monkeys. In contrast, administration of the selective partial D1 agonist SKF38393 did not induce locomotor activity, but rather decreased activity. Choreiform movements were observed only following treatment with L-dopa. Coadministration of the D1 antagonist SCH23390 prevented L-dopa-induced chorea at the time of peak effect. However, a rebound exaggeration of chorea was observed following SCH 23390 at the time when chorea induced by L-dopa alone would normally be subsiding. Unlike chorea, dystonia could be induced by treatment with either L-dopa or (+)-PHNO. Administration of apomorphine failed to significantly induce dystonia, although a small increase was observed with the highest dose. Treatment with SKF38393 actually decreased dystonia. Our findings clearly indicate that D2 receptor stimulation appears essential for antiparkinsonian activity, and also implicate D2 receptors in the genesis of dystonia, but not chorea. D1 receptor stimulation appears to be involved in the genesis of chorea and possibly also dystonia.
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PMID:Differential effects of D1 and D2 agonists in MPTP-treated primates: functional implications for Parkinson's disease. 214 May 95

Selective D1 and D2 dopamine (DA) antagonists and agonists were given to 4 Cebus monkeys who had previously received haloperidol treatment for 4 years. SCH 23390 (a selective D1 antagonist) and raclopride (a selective D2 antagonist) induced identical syndromes consisting of dystonia and oral dyskinesia. Biperiden (an anticholinergic drug) and LY 171555 (a selective D2 agonist) completely antagonized the dystonia and dyskinesia induced by SCH 23390 as well as raclopride. The combined treatment with LY 171555 and SCH 23390 (but not LY 171555 and raclopride) caused pronounced sedation. LY 171555 induced repetitive movements of head, legs and trunk, but no oral dyskinesia. SKF 38393 (a partial D1 agonist) caused slight sedation, minimal oral dyskinesia and a significant reduction in D2 agonist-induced repetitive movements.
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PMID:Selective D1 and D2 receptor manipulation in Cebus monkeys: relevance for dystonia and dyskinesia in humans. 289 Nov 33

While dyskinetic movements have been reported in primates with unilateral excitotoxic lesions following stimulation by dopaminergic agonists, the presence and intensity of the dyskinetic syndromes have varied extensively with size and location of lesion. With the intent of producing a more reliable behavioral model of Huntington disease, anatomically-defined lesions of limited size were produced by magnetic resonance imaging-guided stereotaxic injection of quinolinic acid in specific regions within the caudate and putamen of rhesus monkeys. The location and extent of the lesions were verified by magnetic resonance imaging as well as quantitative positron emission tomography imaging with the dopamine D1 specific receptor ligand SCH 39166 as a marker for striatal output neurons. The quality, frequency and duration of dyskinetic movements were assessed and quantified before and after administration of 0.5 mg/kg apomorphine in multiple test sessions over several months. Selective unilateral lesions in the posterior putamen, but not in the anterior putamen or the head of the caudate, produced marked dystonia and dyskinesia after apomorphine administration. While combined unilateral lesions of the caudate and posterior putamen produced dyskinesia similar to selective posterior putaminal lesions, combined unilateral lesions of the anterior and posterior putamen did not elicit dyskenesia. On the basis of these results, one monkey received a bilateral selective lesion in the posterior putamen. This animal remained healthy and exhibited marked spontaneous Huntington-like chorea spontaneously in the first 48 h after lesioning and persistent apomorphine-induced dyskinesia thereafter. We conclude that bilateral selective excitotoxic lesions of the posterior putamen provide an improved model of the movement disorder of Huntington disease.
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PMID:Selective putaminal excitotoxic lesions in non-human primates model the movement disorder of Huntington disease. 775 72

Dystonia has been proposed to be caused by abnormal input from thalamus to premotor cortex due to altered activity of the striatum projecting by way of the globus pallidus and substantia nigra pars reticulata to the thalamus. However, in the case of idiopathic dystonia, i.e. the most common form of dystonia in humans, there is only limited evidence to support such a neuroanatomic concept. In view of the problems of studying the pathophysiology of idiopathic dystonia in patients, genetically determined animal models of idiopathic dystonia may be used as a practical means of studying brain dysfunctions involved in this movement disorder. The genetically dystonic hamster is an animal model of idiopathic dystonia that displays sustained abnormal movements and postures either spontaneously or in response to mild environmental stimuli. Autoradiographic analysis of dopamine D1 receptor density, using the ligand [3H]SCH 23390, revealed significant decreases of D1 binding in several parts of the striatum and substantia nigra pars reticulata of dystonic hamsters. Binding of the D2 ligand [3H]YM-09151-2 was decreased in the dorsomedial caudate-putamen, but increased in nucleus accumbens. In most other sites studied, no significant changes were found in either [3H]SCH 23390 or [3H]YM-09151-2 binding. By studying groups of dystonic hamsters in the absence and presence of dystonic attacks, it was shown that most changes in D1 and D2 binding were not secondary to abnormal movement but rather due to the dystonic condition of the animals. The study provides evidence of altered dopamine receptor binding in dystonia and confirms the concept that basal ganglia dysfunction may be a primary component of dystonia.
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PMID:Quantitative autoradiography reveals regionally selective changes in dopamine D1 and D2 receptor binding in the genetically dystonic hamster. 868 23

Mutant dystonic hamsters (dt(sz)), a model of primary paroxysmal dystonia, display attacks of generalized dystonia in response to mild stress in an age-dependent manner. Recent studies in dystonic hamsters have revealed decreased densities of dopamine D(1) and D(2) in the dorsal striatum. This finding has been interpreted as a down-regulation in response to enhanced dopamine release because systemic treatments with neuroleptics reduced the severity of dystonia while levodopa exerted prodystonic effects. Therefore, in the present study we investigated the effects of amphetamine as well as of selective D(1) or D(2) receptor agonists and antagonists on the severity of dystonia after systemic administrations and after microinjections into the dorsal striatum. Amphetamine and the dopamine D(2) agonist quinpirole increased the severity of dystonia after systemic and striatal injections, while the dopamine D(1) agonist SKF 38393 exerted only moderate prodystonic effects after systemic administration of a high dose but not after striatal injections. These results suggest that a predominant overstimulation of D(2) receptors is pathogenetically involved in the dystonic syndrome. Combined systemic or striatal administrations of the D(1) and D(2) receptor agonists did not reveal synergistic prodystonic effects at the examined doses. The selective D(1) antagonist SCH 23390 as well as the D(2) antagonist raclopride tended to decrease the severity of dystonia after systemic administration but failed to exert significant effects after striatal injection. The coadministration of ineffective doses of the antagonists SCH 23390 and raclopride, however, exerted an enormous antidystonic efficacy after both systemic and striatal injections. Since striatal injections of compounds which enhance dopaminergic activity aggravated dystonia, while coinjections of dopamine D1 and D2 receptor antagonists reduced the severity of dystonia, the present findings clearly support the hypothesis that striatal dopaminergic overactivity plays a crucial role for the manifestation of dystonic attacks in the hamster model of paroxysmal dystonia.
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PMID:Evidence for striatal dopaminergic overactivity in paroxysmal dystonia indicated by microinjections in a genetic rodent model. 1079 58

High frequency stimulation (HFS) of the subthalamic nucleus (STN) has clinically emerged as a promising approach in the treatment of Parkinson's disease, epilepsy, dystonia as well as compulsive and possibly other mood disorders. The underlying mechanisms are incompletely understood, but are definitely related to high frequency and likely to involve the dopamine (DA)-system. To further test this hypothesis the present study investigated the modulation of STN-HFS-induced circling by systemic and intracerebral injection of drugs acting on DA receptors in naive freely moving rats. Within this experimental setup, unilateral STN-HFS alone induced intensity-dependent circling. Systemic injections of selective D1- (SCH-23390) and D2-((-)-sulpiride) antagonists as well as the mixed D1 and D2 agonist apomorphine dose-dependently reduced STN-HFS-induced rotational behavior. Intracerebral microinjections of (-)-sulpiride but not SCH-23390 decreased circling when injected intrastriatally and increased the number of rotations when injected intranigrally (pars reticulata (SNr)). These data reveal that STN-HFS-induced contralateral circling is differentially modulated by D1 and D2 receptors. While D2 receptor-mediated effects involve the dorso-/ventrolateral striatum and the SNr, D1 receptors probably exert their actions via brain areas outside the striatum and SNr. These findings suggest the nigrostriatal DA-system to be specifically involved in the mediation of STN-HFS-induced motor effects.
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PMID:Subthalamic high frequency stimulation induced rotations are differentially mediated by D1 and D2 receptors. 1508 94

The hph-1 mice have defective tetrahydrobiopterin biosynthesis and share many neurochemical similarities with l-dopa-responsive dystonia (DRD) in humans. In both, there are deficiencies in GTP cyclohydrolase I and low brain levels of dopamine (DA). Striatal tyrosine hydroxylase (TH) levels are decreased while the number of DA neurones in substantia nigra (SN) appears normal. The hph-1 mouse is therefore a useful model in which to investigate the biochemical mechanisms underlying dystonia in DRD. In the present study, the density of striatal DA terminals and DA receptors and the expression of D-1, D-2, and D-3 receptors, preproenkephalin (PPE-A), preprotachykinin (PPT), and nitric oxide synthase (NOS) mRNAs in the striatum and nucleus accumbens and nigral TH mRNA expression were examined. Striatal DA terminal density as judged by specific [3H]mazindol binding was not altered while the levels of TH mRNA were elevated in the SN of hph-1 mice compared to control (C57BL) mice. Total and subregional analysis of the striatum and nucleus accumbens showed that D-2 receptor ([3H]spiperone) binding density was increased while D-1 receptor ([3H]SCH 23390) and D-3 receptor ([3H]7-OH-DPAT) binding density was not altered. In the striatum and nucleus accumbens, expression of PPT mRNA was elevated but PPE-A mRNA, D-1, D-2 receptor, and nNOS mRNA were not changed in hph-1 mice compared to controls. These findings suggest that an imbalance between the direct strionigral and indirect striopallidal output pathways may be relevant to the genesis of DRD. However, the pattern of changes observed is not that expected as a result of striatal dopamine deficiency and suggests that other effects of GTP cyclohydrolase I deficiency may be involved.
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PMID:Alterations in expression of dopamine receptors and neuropeptides in the striatum of GTP cyclohydrolase-deficient mice. 1553 Aug 90


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