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)

Effects of intracerebroventricular (third ventricle) injection of N-methyl-D-aspartate (NMDA) on arterial blood pressure, on heart rate, on arginine vasopressin (AVP) and levels of catecholamines in plasma and on the behaviour of normotensive freely-moving rats have been evaluated. N-Methyl-D-aspartate significantly (P less than 0.01) increased arterial blood pressure and levels of catecholamines and AVP in plasma. With 0.1-1.0 micrograms/rat all animals presented psychomotor agitation, stereotyped movements, hyperexcitability, exophthalmus, dyspnoea, jumping, rearing and teething. The selective antagonist for NMDA receptors, 2-APV injected in the third ventricle, significantly (P less than 0.01) antagonized the hypertension, the increase in levels of catecholamines and AVP in plasma and behavioural effects. An antagonist of alpha 1 adrenergic receptors, prazosin (i.v.), an agonist of alpha 2 adrenergic receptors, clonidine (i.c.v.) and a relatively selective antagonist of V1 subtype of receptor of AVP, CGP 25838 (i.c.v. and i.v.), 15 min before NMDA, significantly (P less than 0.01) decreased the effects induced by the injections of NMDA. On the contrary, an antagonist of opiate receptors, naloxone (i.v.), 15 min before NMDA, significantly (P less than 0.01) increased the NMDA-induced modifications. Pretreatment with the antagonists at these doses, did not significantly modify the basal values of arterial blood pressure and behaviour. Only 2-APV sometimes induced ataxia, lasting about 5 min. This study points out an increase in the central sympathetic efferent activity and in release of AVP involved in the NMDA-induced cardiovascular and behavioural effects.
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PMID:Participation of arginine vasopressin-mediated and adrenergic system-mediated mechanisms in the hypertension induced by intracerebroventricular administration of NMDA in freely moving rats. 135 1

Characteristics of the ambulation-increasing effect of MK-801, a non-competitive NMDA antagonist, were assessed through the coadministration of MK-801 with various central-acting drugs in mice. The MK-801 (0.3 mg/kg, i.p.)-induced ambulation-increment with a slight ataxia was maximum at around 50 min, and ambulation returned to the control level at about 3 hr after the administration. At 1 mg/kg, the mouse's activity transiently increased, followed by a decrease due to a marked ataxia, which was due to neither stereotypy nor convulsion, for 20-50 min, and then increased again; the ambulation-increment continued even at 4 hr after the administration. Coadministration of MK-801 (0.3 mg/kg, i.p.) with either methamphetamine (2 mg/kg, s.c.), cocaine (20 mg/kg, s.c.), GBR-12909 (10 mg/kg, i.p.), scopolamine (0.5 mg/kg, s.c.), caffeine (10 mg/kg, s.c.) or morphine (10 mg/kg, s.c.) produced a significant enhancement of the effect. However, 0.1 mg/kg of MK-801 had no effect on the interaction with these drugs. On the other hand, the ambulation-increasing effect of MK-801 (0.3 mg/kg) was significantly reduced by haloperidol (0.3 and 0.1 mg/kg, s.c.), ceruletide (0.01 and 0.1 mg/kg, i.p.), reserpine (0.05 and 2 mg/kg, s.c., pretreatment 4 hr before) and nimodipine (1 and 3 mg/kg, i.p.), but it was scarcely modified by alpha-methyl-p-tyrosine (100 and 200 mg/kg, i.p., pretreatment 24 hr and 4 hr before), imipramine (20 mg/kg, i.p.), 6R-L-erythro-5,6,7,8-tetrahydro-biopterin (100 mg/kg, i.p.), pilocarpine (1 and 4 mg/kg, s.c.), N6-(L-2-phenylisopropyl)-adenosine (0.03 and 0.1 mg/kg, s.c.) and naloxone (1 and 5 mg/kg, s.c.).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characteristics of the ambulation-increasing effect of the noncompetitive NMDA antagonist MK-801 in mice: assessment by the coadministration with central-acting drugs. 164 Jun 58

We have compared the ability of phencyclidine (PCP)-like or sigma ligands to induce psychomotor effects in primates. In squirrel monkeys, administration of MK-801 (0.001-0.1 mg/kg), PCP (0.03-0.3 mg/kg), (+)-SKF10047 (0.001-3.0 mg/kg) or (-)-SKF10047 (0.1-10 mg/kg) induced ataxia, head weaving and bradykinesia. In contrast, treatment with the selective sigma ligand (+)-pentazocine using doses up to 20 mg/kg failed to induce any overt behaviours. The order of potency for induction of these behaviours was: MK-801 greater than PCP greater than (+)-SKF10047 greater than (-)-SKF10047 much greater than (+)-pentazocine. In rhesus monkeys treatment with MK-801 (0.01-0.04 mg/kg), PCP (0.05-0.2 mg/kg), (+)-SKF10047 (0.75-3.0 mg/kg) or (+)-pentazocine (1-10 mg/kg), disrupted performance of a spatial delayed response task. The potency to induce cognitive disruption was positively correlated with affinity for [3H]MK-801, but not [3H](+)-SKF10047, binding sites in vitro. These findings indicate that the psychomotor and cognitive effects of PCP-like and sigma ligands in primates are mediated through interactions at NMDA, not sigma, receptors.
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PMID:Psychomotor activity and cognitive disruption attributable to NMDA, but not sigma, interactions in primates. 164 81

In the present studies the behavioral-pharmacological effects of kynurenine and its metabolite kynurenic acid were investigated after intracerebroventricular (ICV) microinjection in rats. Kynurenine (0.1 and 0.2 mumol ICV) produced slight behavioral changes, but its metabolite kynurenic acid (0.2 mumol ICV) induced marked ataxia, stereotyped behavior and muscular hypotonia in a dose-dependent manner. The kynurenic acid-induced neurological symptoms were partially inhibited but not eliminated by ICV pretreatment with D-serine (0.5, 2.5, 5 mumol), which is a selective agonist at the strychnine-insensitive glycine binding site of the NMDA-receptor complex. Our results support the following conclusions: 1) kynurenine (0.1 or 0.2 mumol, ICV) results in slight stereotypy and ataxia, but the speed of its metabolism to kynurenic acid in this paradigm is not sufficient to produce concentrations of kynurenic acid, which are able to elicit marked ataxia and stereotypy; 2) the duration of kynurenic acid-induced behavioral abnormalities is correlated with the length of disappearance of micro-injected kynurenic acid from brain tissue; 3) D-serine which is an agonist at the glycine site linked to the NMDA complex, partially antagonizes but does not eliminate the neurological disturbances induced by ICV kynurenic acid injection.
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PMID:Intracerebroventricular injection of kynurenic acid, but not kynurenine, induces ataxia and stereotyped behavior in rats. 227 66

The effects of acute and subchronic administration of the noncompetitive NMDA receptor antagonist MK-801 on the duration and severity of amygdaloid-kindled seizures in rats were determined to evaluate its anticonvulsant activity. Both the highest acute (1000 micrograms/kg) and subchronic regimens (2 x 300 micrograms/kg, 7 days) produced significant reductions in the seizure stage and afterdischarge duration. Although ataxia may have affected the seizure stage, MK-801 attenuated the primary afterdischarge suggesting anticonvulsant effects in the fully amygdaloid-kindled rat. Since tolerance develops to the behavioral effects of MK-801, other noncompetitive NMDA antagonists related to MK-801 seem to warrant evaluation as anticonvulsants.
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PMID:Effects of the NMDA receptor antagonist MK-801 against amygdaloid-kindled seizures in the rat. 253 32

MK-801 is a ligand at phencyclidine recognition sites associated with NMDA-coupled cation channels, where it acts as a potent noncompetitive antagonist of central glutamate/aspartate (NMDA-type) receptors. Low doses (10-100 micrograms/kg IP) produced a dose-related and prolonged (greater than 1 h) enhancement of variable-interval self-stimulation responding. Higher doses (300 micrograms/kg) caused flaccid ataxia and disrupted responding. Ketamine HCl (3.0-100 mg/kg IP), a dissociative anaesthetic binding to the phencyclidine site, produced a similar response pattern, but facilitation was less prolonged and occurred over a narrower dose range. Kynurenic acid (3.0-300 mg/kg IP), a nonselective competitive antagonist of glutamate receptors, produced only depression of responding, possibly the result of kynurenate-induced blockade of central kainate and/or quisqualate receptors. The behavioural stimulant effects of MK-801 appear to be an intrinsic and essential feature of selective NMDA antagonists, and these effects of MK-801 differ qualitatively and quantitatively from the well-known facilitatory effects of dopamine-dependent stimulants.
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PMID:The effect of MK-801 and other antagonists of NMDA-type glutamate receptors on brain-stimulation reward. 255 Sep 89

Behavioral and in vitro receptor binding methods were used to evaluate and compare the effects of FR115427 ((+)-l-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride) with those of MK801, a non-competitive NMDA antagonist. FR115427 inhibited NMDA-induced convulsions in mice by intracerebroventrical(ICV) and systematic injection. FR115427 was found to be about ten times less potent than MK801. Furthermore, the inhibitory effect of FR115427 and MK801 on NMDA-induced convulsions was evaluated in time course studies in mice. MK801 exhibited a more sustained anticonvulsive activity than FR115427. In addition, PCP-like behaviors were examined in mice after ICV injection of these compounds. At the lowest dose FR115427 significantly increased locomotor activity, although the effect of this compound was about hundred times less potent than that of MK801. At higher dose a more complex pattern of behavior, e.g. head-movement and eventually ataxia was observed. In binding assays with rat brain membranes, FR115427 inhibited the binding of (3H)TCP (IC50 = 0.249 microM) and (3H)MK801 (IC50 = 0.312 microM) but did not inhibit the binding of (3H)CPP or (3H)glycine. These results suggest that FR115427 is a novel non-competitive NMDA antagonist that acts on a binding site located within the NMDA receptor associated ion channel.
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PMID:Behavioral studies on FR115427, a novel selective N-methyl-D-aspartate antagonist. 775 64

The glycine B receptor partial agonists L 687,414, D-cycloserine and (+)-HA 966, and the glycine B receptor antagonists MDL 29,951 and 5,7-dichloro-2,4 dihydroxy-3-phenyl-quinoline dione (DCPQ) dose-dependently inhibited the late phase (LP) of formalin-induced licking (FIL) elicited by intraplantar formalin in mice at doses exerting little motor disruption in the rotarod test. In distinction, the early phase (EP) of FIL and the writhing response to intra-abdominal acetic acid were little influenced and, irrespective of stimulus intensity, they failed to modify the tail-flick response to phasic, thermal or mechanical stimulation of the tail. In contrast to glycine B ligands, competitive antagonists at the NMDA receptor recognition site (CPP, CGS 19755, CGP 34879 and 39551) and blockers of the associated ion channel ((+)-MK 801, (-)-MK 801, memantine and ketamine) all blocked both the LP and EP of FIL and induced ataxia at comparable doses. In conclusion, normalization of transmission at NMDA receptors by inhibition of the coupled glycine B site preferentially elicits antinociception against prolonged (chemical) noxious stimulation in the absence of a marked influence upon motor coordination.
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PMID:Chemically-diverse ligands at the glycine B site coupled to N-methyl-D-aspartate (NMDA) receptors selectively block the late phase of formalin-induced pain in mice. 781 23

1. GYKI 52466 is a benzodiazepine derivative that has muscle relaxant and anticonvulsant properties thought to be mediated by highly selective, noncompetitive antagonism of non-NMDA receptors. However, recent electrophysiological data showed that, in addition to non-NMDA receptors, the GABAA-receptor associated benzodiazepine site is involved in the depressant effect of GYKI 52466 on spinal reflex transmission. In view of the structural similarities between the 2,3 benzodiazepine derivative GYKI 52466 and 1,4-benzodiazepines such as diazepam, the benzodiazepine site of GABAA receptor complex could also be involved in the anticonvulsant activity of GYKI 52466, which has not yet been proven. This prompted us to study the effect of the benzodiazepine receptor antagonist, flumazenil, on anticonvulsant and adverse effects of GYKI 52466 in different seizure models in mice. The non-NMDA antagonist, NBQX and diazepam were used for comparison. 2. Seizure threshold models for different types of generalized seizures were used. The threshold for maximal (tonic) electroshock seizures (MES) was significantly increased by GYKI 52466 (10-20 mg kg-1), NBQX (80-120 mg kg-1) and diazepam (5 mg kg-1) shortly after i.p. drug administration. The same dose-range of the non-NMDA antagonists also significantly increased the threshold for myoclonic and clonic seizures induced by i.v. infusion of pentylenetetrazol (PTZ), although the magnitude of threshold increases obtained with the respective drugs, differed, at least in part, from that seen in the MES experiments. GYKI 52466 was clearly less potent in increasing PTZ thresholds for myoclonic and clonic seizures than on the MES threshold, while NBQX exerted about the same potency in both models. In contrast to the non-NMDA antagonists, diazepam was capable of increasing themyoclonic and clonic PTZ seizure threshold at much lower doses than the MES threshold. The PTZ threshold for tonic seizures was markedly increased by GYKI 52466, while NBQX and diazepam were clearly less potent in this respect.3. With respect to adverse effects, GYKI 52466 and NBQX induced significant seizure threshold increases in the different seizure models only at doses which caused sedation and ataxia, while diazepam increased the myoclonic and clonic PTZ seizure threshold at doses below those inducing motor impairment.4. Flumazenil (5-20 mg kg-1) antagonized the anticonvulsant and adverse effects of diazepam but not GYKI 52466. Instead, the anticonvulsant effect of GYKI 52466 was potentiated by flumazenil in some experiments. The anticonvulsant activity of NBQX was slightly reduced by flumazenil in the MES model but not in the PTZ test.5. The data indicate that the GABAA receptor-associated benzodiazepine site is not critically involved in anticonvulsant or adverse effects of GYKI 52466. However, both GYKI 52466 and NBQX were unable to increase seizure thresholds at doses below those inducing sedation and motor impairment,thus demonstrating that non-NMDA antagonists lack a selective anticonvulsant action in standard models of generalized seizures.
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PMID:Effects of the non-NMDA antagonists NBQX and the 2,3-benzodiazepine GYKI 52466 on different seizure types in mice: comparison with diazepam and interactions with flumazenil. 788 91

SDZ EAA 494 (D-CPPene) was characterized as a competitive NMDA antagonist, having a pA2 value against NMDA depolarizations in frog spinal cord and rat neocortex of 6.7-6.8 and a pKi of 7.5 in a [3H]CGP39653 binding assay, with no action on other receptors or amine reuptake. The compound was orally active in rodent maximal electroshock models with an ED50 of around 16 mg/kg, was protective in rats even 24 hours after oral application and had an oral therapeutic index of around 8. Muscle relaxation, ataxia, flattened body posture and reduced acquisition of a passive avoidance task, suggesting potential effects on memory formation, occurred at supra-anticonvulsant doses in rodents, with PCP-like stimulatory effects produced only by high i.p. doses or constant i.v. infusions. This favourable profile is discussed in relation to the negative outcome of a recent trial of the compound in patients with intractable epilepsy. The conclusion is drawn that standard models for screening new anticonvulsants are inappropriate to seeking drugs active in patients with a protracted convulsive history. The anti-ischaemic action of SDZ EAA 494 encourages further testing in brain trauma, in which the anticonvulsant action of the compound may be an added benefit.
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PMID:The pharmacology of SDZ EAA 494, a competitive NMDA antagonist. 789 35


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