Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anxiolytic agents disinhibit suppressed behaviors in rodents in preclinical models of anxiety such as the non-conditioned social interaction and elevated plus maze assays and the conditioned conflict Cook and Davidson procedure. The (+) and (-) enantiomers of (+/-)-3-amino-1-hydroxy-2-pyrrolidinone (HA-966) have been resolved and revealed that R-(+)-HA-966 significantly disinhibits both non-conditioned and conditioned suppressed behavior similar to the benzodiazepine diazepam, while the S-(-) enantiomer was devoid of anxiolytic activity and only produced behavioral sedation. Furthermore, R-(+)-HA-966 lacked side-effects in rodents commonly associated with the administration of benzodiazepines such as motor incoordination and ataxia, significant interactions with ethanol, and amnesia. These data suggest that R-(+)-HA-966, an antagonist at the strychnine-insensitive glycine/NMDA receptor site, was anxioselective and lacked some of the side-effects associated with benzodiazepine anxiolytics.
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PMID:Stereoselective R-(+) enantiomer of HA-966 displays anxiolytic effects in rodents. 135 34

The anticonvulsant and behavioural actions of CGP 37849 and CGP 39551, two novel competitive NMDA receptor antagonists, were examined in fully amygdala kindled rats following systemic administration. Only weak anticonvulsant effects were observed following either i.p. or i.v. injection of the antagonists. Moreover, behavioural abnormalities (ataxia, hyperactivity, muscular hypotonia) were apparent at all anticonvulsant doses. These results suggest that CGP 37849 and CGP 39551 may be of limited therapeutic usefulness against complex partial seizures in man, the seizure type showing greatest refractoriness to presently available medication.
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PMID:Weak anticonvulsant activity of CGP 37849 and CGP 39551 against kindled seizures following systemic administration. 135 38

The non-competitive NMDA receptor antagonist, MK-801 (dizocilpine), induces in rats a characteristic behavioural syndrome with ataxia, stereotypies and hyperlocomotion. At least part of this behavioural syndrome is thought to be related to interactions between glutamatergic and dopaminergic neurotransmission. Based on recent biochemical evidence that serotonin (5-HT) might also be involved in the effects of MK-801 several 5-HT receptor ligands were tested for effects on MK-801-induced behaviours. The 5-HT1A receptor ligands, ipsapirone and NAN-190, which are known to display antagonist-like properties in functional models of postsynaptic 5-HT1A receptor activity attenuated or blocked the hyperlocomotion and head weaving observed after administration of MK-801, whereas the 5-HT2 receptor antagonist, ritanserin, was ineffective in this respect. The dopamine receptor antagonist, haloperidol, and the alpha 1-adrenoceptor antagonist, prazosin, also attenuated behaviours induced by MK-801. In contrast to its effects on stereotypies induced by MK-801, ipsapirone potentiated rather than attenuated the stereotyped behaviour induced by the dopamine receptor agonist, apomorphine, indicating that antagonism of MK-801-induced stereotypies by ipsapirone may not be related to the dopaminergic system. The data indicate that, in addition to catecholaminergic systems, serotonergic neurotransmission is significantly involved in the mechanisms by which MK-801 alters behaviour in rats.
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PMID:The behavioural effects of MK-801 in rats: involvement of dopaminergic, serotonergic and noradrenergic systems. 135 90

The influence of verapamil and flunarizine on phencyclidine-induced effects has been studied in adult male rats. Both verapamil (25 and 100 micrograms/10 microliters, i.c.v.) and flunarizine (40 and 60 mg/kg, i.p.) significantly reduced behavioural (mean intensity of ataxia, mean duration of head weaving) and the EEG (increase in the mean voltage of background activity of the EEG) effects induced by phencyclidine 5 mg/kg (i.p.). It was reported previously that nimodipine and diltiazem significantly potentiate effects induced by phencyclidine. The contrasting results obtained with verapamil and flunarizine, suggest that these drugs may modulate effects induced by phencyclidine by acting at sites other than NMDA receptor-coupled "L"-type calcium channel.
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PMID:Verapamil and flunarizine inhibit phencyclidine-induced effects: an EEG and behavioural study in rats. 147 25

The akinesia induced by reserpine in mice was effectively reversed by the dopamine D1 receptor agonists SKF 38393 (5-30 mg/kg IP) and CY 208-243 (1-5 mg/kg IP), and by the mixed D1/D2 agonist pergolide (5 mg/kg SC), but less well by the D2 agonists lisuride, PHNO, LY 171555 and RU 24213 (each at 5 mg/kg SC) and not at all by the NMDA receptor antagonist MK 801 (0.1-10 mg/kg IP). MK 801 potentiated D1-dependent locomotion, but always suppressed rearing and grooming. D2-dependent locomotion was inhibited by MK 801. The D2 agonist RU 24213 was antagonised by as little as 6.25 micrograms/kg MK 801, while PHNO and LY 171555 were antagonised by 0.1 mg/kg MK 801. Lisuride was not inhibited by up to 1.6 mg/kg MK 801. Importantly, all animals showed signs of incapacitation with MK 801 in certain elements of their behaviour, most notably ataxia and hind limb abduction. Thus whilst NMDA receptor blockade can facilitate the restoration of movement by dopamine D1 (though not D2) agonists in monoamine-depleted mice, the fluency of the motor response is adversely affected.
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PMID:Motor responses to dopamine D1 and D2 agonists in the reserpine-treated mouse are affected differentially by the NMDA receptor antagonist MK 801. 153 57

HU211 is a novel synthetic derivative of tetrahydro-cannabinol (THC), the active marijuana ingredient. The stereochemistry of HU211 is enantiomeric to that of THC. In contrast to THC, HU211 is not psychotropic. This agent exhibits other types of biological activities; it is a non-competitive NMDA receptor blocker and has antinociceptive activity when injected with cupric chloride. This study examined its effects in autotomy, a behavioral model of neuropathic pain. Autotomy, a behavior of self-mutilation of denervated areas, was induced in Sabra rats by cutting the sciatic and saphenous nerves. We found that injections of HU211 (2.5 mg/kg) with cupric chloride (0.8 mg/kg) every 2nd day markedly suppressed autotomy during the injection period by delaying its average onset day and reducing the incidence of severe autotomy. Moreover, suppression of autotomy was retained in the postinjection period (for at least 30 days) but only when the drug was injected intraperitoneally. Lesser effects were achieved by subcutaneous injections. Cupric chloride or HU211 alone were ineffective. The general behavior and open field motor activity indicated that the effects of HU211 with Cu++ on autotomy were not due to sedation or ataxia but presumably due to antinociception mediated by NMDA receptor blockade.
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PMID:Suppression of neuropathic pain behavior in rats by a non-psychotropic synthetic cannabinoid with NMDA receptor-blocking properties. 166 28

The orally active competitive N-methyl-D-aspartate (NMDA) receptor antagonists CGP 37849 (DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid) and its ethyl ester CGP 39551 were evaluated in amygdala-kindled rats, a model for complex partial and secondarily generalized seizures. Anticonvulsant and behavioral effects of these novel compounds were compared with those of the noncompetitive NMDA receptor antagonist MK-801 [(+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-imin e] and the antiepileptic drug carbamazepine, one of the major drugs for treatment of partial and generalized seizures in humans. For comparative evaluation, the compounds were injected i.p. at the following doses: 1 to 10 mg/kg (CGP 37849 or CGP 39551), 0.05 to 0.3 mg/kg (MK-801) and 20 to 40 mg/kg (carbamazepine), respectively. In contrast to carbamazepine, CGP 37849, CGP 39551 and MK-801 exerted only weak anticonvulsant effects in fully kindled rats and did not increase the focal seizure threshold. The weak anticonvulsant effects of the NMDA receptor antagonists in kindled rats were associated with profound untoward behavioral effects. The behavioral syndrome induced by the NMDA receptor antagonists in kindled rats was characterized by marked ataxia, hyperactivity and, in case of CGP 37849 and MK-801, stereotypies, such as head weaving. The low or absent effectiveness of the novel NMDA receptor antagonists against kindled seizures suggests that these compounds will not be clinically useful antiepileptics against partial and secondarily generalized seizures. Furthermore, in view of the recent clinical findings on psychotomimetic effects of MK-801 in epileptic patients, the similarities in the excitatory effects produced by CGP 39551, CGP 37849 and MK-801 in kindled rats may indicate that competitive NMDA receptor antagonists may also produce psychotomimetic effects in humans.
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PMID:Anticonvulsant and behavioral effects of two novel competitive N-methyl-D-aspartic acid receptor antagonists, CGP 37849 and CGP 39551, in the kindling model of epilepsy. Comparison with MK-801 and carbamazepine. 167 93

The novel competitive N-methyl-D-aspartate (NMDA) receptor antagonist DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849) was found to produce a phencyclidine (PCP)-like behavioral syndrome (ataxia, locomotion, stereotypies) in amygdala-kindled rats, whereas the amphetamine-like behavioral alterations of the syndrome (locomotion, stereotypies) were only infrequently seen in nonkindled rats. In dose-response experiments in kindled and nonkindled rats, behavioral effects were scored using a ranked intensity scale, and the behaviors and behavioural scores determined after CGP 37849 were compared with those determined after i.p. administration of the noncompetitive NMDA receptor antagonist dizocilpine maleate (MK-801). In kindled rats, 20 mg/kg of CGP 37849 produced about the same scores for hyperlocomotion and head weaving as 0.1 mg/kg of MK-801. Kindled rats exhibited higher behavioral scores than nonkindled rats, especially in the case of CGP 37849. The behavioral effects produced by CGP 37849 in kindled rats were almost indistinguishable from the PCP-like behavioral effects induced by MK-801, indicating that CGP 37849 indeed produces a PCP-like pattern of behavior in kindled rats. Hyperlocomotion and head weaving induced by CGP 37849 in kindled rats could be attenuated or totally prevented by pretreatment with ipsapirone, a partial agonist/antagonist at postsynaptic 5-hydroxytryptamine (5-HT) receptors of the 5-HT1A subtype. Furthermore, these behavioural effects were attenuated or blocked by the dopamine antagonist haloperidol and the alpha-1 adrenoceptor antagonist, prazosin. The data demonstrate that kindling induces a hypersensitivity to PCP-like behavioral effects of competitive and noncompetitive NMDA receptor antagonists, which could relate to the recent finding of increased function of NMDA receptors following kindling.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The novel competitive N-methyl-D-aspartate (NMDA) antagonist CGP 37849 preferentially induces phencyclidine-like behavioral effects in kindled rats: attenuation by manipulation of dopamine, alpha-1 and serotonin1A receptors. 167 88

The effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 and the novel competitive NMDA receptor antagonist CGP 39551 on levels of 11 amino acids, including several excitatory and inhibitory neurotransmitters, were studied in 12 brain regions of rats. Both drugs were administered at doses which produced comparable behavioural effects (ataxia, hyperactivity). Amino acids were determined in brain tissue by high-performance liquid chromatography after o-phthaldialdehyde precolumn derivatization. MK-801 (0.1 mg/kg, i.p.) moderately increased the concentration of glutamate and GABA in several brain regions. Other amino acids (glutamine, taurine, asparagine, alanine, serine) were only altered in single brain regions, or were not altered at all (aspartate, glycine, threonine, arginine). In contrast to MK-801, CGP 39551 (10 mg/kg, i.p.) increased glutamate levels only in the cerebellum, and produced no significant alterations in levels of GABA. The data demonstrate differences in alterations of amino acid levels in response to competitive and non-competitive NMDA receptor antagonists and support the assumption that competitive NMDA antagonists may be more selective than non-competitive antagonists.
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PMID:Regional alterations in brain amino acids after administration of the N-methyl-D-aspartate receptor antagonists MK-801 and CGP 39551 in rats. 167 57

The effects of competitive and noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists were evaluated in an inbred line of Syrian golden hamsters, in which sustained dystonic postures of limbs and trunk can be initiated by handling or mild environmental stimuli. In this model of paroxysmal dystonia, the noncompetitive NMDA receptor antagonists memantine and MK-801 (dizocilpine) delayed the progression of dystonic attacks in a dose-dependent fashion. The novel competitive NMDA receptor antagonist CGP 37849 (DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid) was more effective than memantine and MK-801, because it retarded not only the progression but also reduced the severity of the dystonic movements. All compounds exhibited antidystonic effects at doses which did not cause marked ataxia or sedation. The data indicate that NMDA receptor antagonists might be interesting candidates for treatment of dystonia.
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PMID:Antidystonic effects of the NMDA receptor antagonists memantine, MK-801 and CGP 37849 in a mutant hamster model of paroxysmal dystonia. 168 81


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