dizocilpine-maleate and Movement-Disorders

Ischemic stroke is the most frequent cause of persistent neurological disability in Western societies. New treatment strategies are required and effective in vivo models are crucial to their development.. The current study establishes a novel in vivo rat model of focal striatal ischemia using the vasoconstrictive agent N5-(1-iminoethyl)-L-ornithine (L-NIO). Adult male Sprague Dawley rats received a unilateral intrastriatal infusion of L-NIO in combination with jugular vein occlusion.. L-NIO infusion was associated with zero mortality, low surgical complexity and a reproducible infarct, providing advantages over established models of focal ischemia. The mean infarct volume of 8.5±5.3% of the volume of the contralateral striatum resulted in blood-brain barrier dysfunction, neuronal hypoxia and ongoing neurodegeneration. Further characteristics of ischemic stroke were exhibited, including robust microglia/macrophage and astroglial responses lasting at least 35 days post-ischemia, in addition to chronic motor function impairment.. When compared to other models such as the MCAo models, the consistency in regions affected, high success rate, zero mortality, reduced surgical complexity and minimal welfare requirements of the L-NIO model make it ideal for initial high-throughput investigations into preclinical efficacy and proof of principle studies of acute ischemic stroke interventions.. We propose that the L-NIO rat model of focal striatal ischemia does not replace the use of other ischemic stroke models. Rather it provides a new, complementary tool for initial preclinical investigations into the treatment of ischemic stroke.

Topics: Animals; Blood-Brain Barrier; Brain Infarction; Brain Ischemia; Corpus Striatum; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gene Expression Regulation; Jugular Veins; Male; Movement Disorders; Nerve Degeneration; Nerve Tissue Proteins; Neurons; Neuroprotective Agents; Ornithine; Rats; Rats, Sprague-Dawley; Time Factors

The purpose of this study was to investigate the temporal pattern of NMDA receptors antagonist-MK-801 on motor behaviour parameters in gerbils submitted to different duration of global cerebral ischemia. The common carotid arteries of gerbils were occluded for 5, 10 or 15min. Gerbils were given MK-801 (3mg/kg i.p.) or saline immediately after the occlusion in normothermic conditions prior to testing. Motor activity was registered 1, 2, 4, 7, 14, 21 and 28 days after reperfusion during 60min by open field test. At the same time, the effect of NMDA receptor blockade was followed in vivo by monitoring the neurological status of whole animals or at the cellular level by standard light and confocal microscopy on brain slices. Post-ischemic gerbils quickly developed hypermotor response with the most intensity in animals submitted to 15min ischemia. MK-801 administrated immediately after ischemia significantly decreased this hyperactivity. In all ischemic-treated animals, behavioural suppression by MK-801 was observed already 1 day after occlusion and was lasting as far as observed ischemia-dependent hypermotor responses. Beneficial effect of MK-801 was also confirmed by morphological and neurological status data. These findings suggest that sustained ischemia-induced hyperactivity is related to abnormalities in NMDA glutamatergic function, as well as its manifestation could be completely abolished by NMDA receptor blockade immediately after ischemic insult.

Topics: Analysis of Variance; Animals; Behavior, Animal; Brain Ischemia; Corpus Striatum; Disease Models, Animal; Dizocilpine Maleate; Gerbillinae; Male; Motor Activity; Movement Disorders; Neurologic Examination; Neuroprotective Agents; Reperfusion; Stereotyped Behavior; Time Factors

Recent anatomical studies showed the presence of cerebellar and basal ganglia connections. It is thus conceivable that the cerebellum may influence the striatal synaptic transmission in general, and synaptic plasticity in particular.. In the present neurophysiological investigation in brain slices, we studied striatal long-term depression (LTD), a crucial form of synaptic plasticity involved in motor learning after cerebellar lesions in rats.. Striatal LTD was fully abolished in the left striatum of rats with right hemicerebellectomy recorded 3 and 7 days following surgery, when the motor deficits were at their peak. Fifteen days after the hemicerebellectomy, rats had partially compensated their motor deficits and high-frequency stimulation of excitatory synapses in the left striatum was able to induce a stable LTD. Striatal plasticity was conversely normal ipsilaterally to cerebellar lesions, as well as in the right and left striatum of sham-operated animals.. These data show that the cerebellum controls striatal synaptic plasticity, supporting the notion that the two structures operate in conjunction during motor learning.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Behavior, Animal; Cerebellum; Corpus Striatum; Dizocilpine Maleate; Electric Stimulation; Excitatory Amino Acid Antagonists; Functional Laterality; Hemispherectomy; In Vitro Techniques; Long-Term Synaptic Depression; Motor Activity; Movement Disorders; Neural Pathways; Rats; Synaptic Transmission; Time Factors

We have recently described two rat mutants, ci2 and ci3, in which abnormal lateralized rotational behavior and locomotor hyperactivity occur either spontaneously or in response to external stimuli, such as new environment. While cochlear and vestibular defects are found in ci2 rats, ci3 rats do not exhibit any inner ear abnormalities. Both mutants show abnormal lateralities in striatal dopamine and in the density of dopaminergic neurons in substantia nigra or ventral tegmental area, which may be involved in the behavioral phenotype of these rats. In line with this hypothesis, the circling behavior of the ci2 and ci3 mutants is intensified by amphetamine. In the present study, we evaluated the effects of dopamine receptor blockade on the abnormal behaviors of ci2 and ci3 rats. Haloperidol blocked the hyperactivity in both mutants, but this was most likely due to the known inhibitory effect on locomotion by this drug. When animals were observed during the light phase, the abnormal rotational behavior of the mutants was not significantly affected by haloperidol, whereas the dopamine D2 receptor-preferring antagonist raclopride significantly reduced rotations in ci2 rats. When the behavior of the ci3 rats was video-monitored during the dark phase, circling was significantly inhibited by haloperidol. The most striking difference between the two mutants was that ci2 rats were less susceptible than the unaffected littermates to the cataleptogenic effects of haloperidol and raclopride, whereas no such difference was observed in ci3 rats. These data demonstrate that, although there are several similarities between the ci2 and ci3 rat mutants, their cataleptogenic response to dopamine receptor blockade strikingly differs. The comparative evaluation of these two rat mutants may help to increase our understanding of the relationship between developmental anomalies of cerebral asymmetry and brain disorders.

Topics: Analysis of Variance; Animals; Behavior, Animal; Dizocilpine Maleate; Dopamine Antagonists; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Hyperkinesis; Locomotion; Movement Disorders; Rats; Rats, Inbred Strains; Rats, Mutant Strains; Rotation; Stereotyped Behavior; Time Factors

Cognitive dysfunction plays an important role in mental disorders like schizophrenia and may involve inadequate glutamatergic signalling in different regions of the brain, mediated by e.g. glutamatergic N-methyl-D-aspartate (NMDA) receptors. In rodents, NMDA receptor antagonists often increase motor activity; in addition they induce a more primitive and undifferentiated behavioural pattern, which we believe may correspond to some of the cognitive defects seen in schizophrenia. In the present study, the movement pattern of mice treated with the uncompetitive NMDA receptor antagonist MK-801 in conjunction with six antipsychotic agents, some with reported clinical effects on cognition, was characterised and quantified. The classical neuroleptic drugs chlorpromazine and trifluoperazine, the atypical antipsychotic agents ziprasidone and olanzapine, the gamma-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-receptor potentiator CX516 and the serotonin (5-HT)2A-antagonist M100907 were tested. In accordance with previous observations, MK-801 was found to induce a primitive and monotonous behavioural pattern dominated by forward locomotion; spatial movements, the number of switches between the states moving and stationary, and rearing frequency were reduced. All test substances counteracted MK-801-induced hyperactivity, but differed in their ability to improve behavioural quality. Chlorpromazine and trifluoperazine were unable to restore behavioural diversity while ziprasidone, olanzapine, CX516 and M100907 restored it to varying degrees. A striking similarity in movement pattern was seen between the hypoglutamatergic mice treated with the AMPA-receptor agonist CX516, and those receiving the 5HT2A-antagonist M100907.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Cognition; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Mice; Movement Disorders; Multivariate Analysis; Statistics, Nonparametric

The aim of the study was to assess the contribution of central dopaminergic and glutamatergic systems to the age-dependent loss of motor functions in rats. Rats of three age groups were compared: young (3-5-month-old), middle-aged (20-21-month-old) and old (29-31-month-old). The obtained results showed an age-dependent decline in the electromyographic (EMG) resting and reflex activities in the gastrocnemius and tibialis anterior muscles, as well as in the T-maze performance. Although these disturbances were accompanied with significant age-dependent decreases in the binding to NMDA, AMPA and dopamine D2 receptors, and a decline in the number of nigral dopamine neurons, they were significantly correlated with the loss of the binding to NMDA receptors only. The reduction in T-maze performance with aging was additionally correlated with a decrease in motor functions (EMG activity). The study suggests a crucial role of the loss of NMDA receptors in age-dependent motor disabilities, as well as in disturbances measured in the T-maze.

Topics: Aging; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Ankle Joint; Biomarkers; Biomechanical Phenomena; Brain Mapping; Cell Count; Dizocilpine Maleate; Dopamine; Electromyography; Female; Glutamic Acid; Learning Disabilities; Maze Learning; Movement Disorders; Muscle, Skeletal; Nerve Tissue Proteins; Pliability; Psychomotor Performance; Raclopride; Rats; Rats, Wistar; Reaction Time; Receptors, AMPA; Receptors, Dopamine D2; Receptors, N-Methyl-D-Aspartate; Substantia Nigra; Tyrosine 3-Monooxygenase

Administration of MK-801 or IEM-1754 prevented akinesia in mice induced by reversing rotation, not less effectively than scopolamine. Quaternary adamantane derivative IEM-1857 was ineffective. IEM-1925 enhanced the locomotor disturbance induced by reversing rotation due, probably, to different spectrum of its antiglutamate action. The data obtained suggest involvement of glutamate synaptic transmission in development of locomotor disturbances of a vestibular origin.

Topics: Adamantane; Animals; Dizocilpine Maleate; Drug Evaluation, Preclinical; Excitatory Amino Acid Antagonists; Male; Mice; Mice, Inbred Strains; Movement Disorders; Muscarinic Antagonists; Receptors, Glutamate; Rotation; Scopolamine; Time Factors

The present study examined the postural effects of the local application of glutamatergic antagonists unilaterally into the subthalamic nucleus (STN), on haloperidol-induced akinesia in rats. After intracerebral injections of MK-801, a selective antagonist of N-methyl-D-aspartate (NMDA) receptor, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) disodium, a selective alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor antagonist, or vehicle, unilaterally into the STN, haloperidol was administered systemically and the elicited behaviors were assessed quantitatively. In rats which received injections of MK-801 or CNQX, but not vehicle, unilaterally into the STN, the administration of haloperidol induced contraversive dystonic posturing. The severity of the deviated posturing was dose-dependent. The present findings revealed that the overactivity of the STN under conditions of dopamine blockade is suppressed by interruptions of glutamatergic inputs, mediated via both NMDA or AMPA receptors, to the STN. Therefore, the present study may provide functional evidence in support of a recently proposed hypothesis, that not only disinhibition from the inhibitory globus pallidus efferents but also excitatory glutamatergic inputs to the STN actually contribute to the overactivity of the STN under dopamine-depleted conditions.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Analysis of Variance; Animals; Anti-Dyskinesia Agents; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Functional Laterality; Haloperidol; Male; Movement Disorders; Posture; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission; Thalamic Nuclei

One of the crucial breakthroughs in research on parkinsonism was the observation of circling behaviour in rodents after unilateral intranigral injection of 6-hydroxydopamine. This Ungerstedt model remains one of the basic animal models of Parkinson's disease. We report here the first mutant rat strain with abnormal circling behaviour and several other features reminiscent of the Ungerstedt Parkinson model. The neurological disorder in the novel mutant rat strain is determined monogenetically by a recessive autosomal gene termed circling (ci). Mutant rats of both genders exhibit an intense asymmetric circling in an open-field or rotometer, which is enhanced by treatment with amphetamine. Neurochemical determinations show that mutants of both genders have significantly lower concentrations of dopamine and dopamine metabolites in the striatum ipsilateral to the preferred direction of rotation. Furthermore, in a forelimb-reaching test for assessing the skilled motor capacities of rats, ci rats show a marked deficit on the side contralateral to the preferred direction of turning, which is analogous to motor deficits previously described for rats subjected to unilateral 6-hydroxydopamine lesions. The new mutant rat strain thus exhibits remarkable similarities to the Ungerstedt model and could be used to study the endogenous processes, particularly the genetic components, that might eventually lead to progressive motor dysfunctions.

Topics: Amphetamine; Animals; Antiparkinson Agents; Apomorphine; Behavior, Animal; Brain Chemistry; Central Nervous System Stimulants; Dizocilpine Maleate; Dopamine; Excitatory Amino Acid Agonists; Female; Forelimb; Male; Motor Activity; Motor Skills; Movement Disorders; Mutation; Rats; Rats, Inbred Lew; Stereotyped Behavior

Dextromethorphan (DM, 40 or 80 mg/kg, i.p.) and MK-801 (3 or 10 mg/kg, i.p.) were compared in their ability to prevent the depletion of choline acetyltransferase (ChAT) activity in the rat striatum following intrastriatal injection of quinolinic acid. DM did not reduce striatal ChAT depletion following injection of either 300 or 150 nmol of quinolinic acid. Following injection of 300 nmol of quinolinic acid, MK-801 significantly reduced striatal ChAT depletion at a dose of 3 mg/kg and completely prevented striatal ChAT depletion at a dose of 10 mg/kg. In contrast to the potent neuroprotective action of MK-801, DM does not protect striatal cholinergic neurons from an acute challenge by an NMDA receptor agonist.

Topics: Animals; Choline O-Acetyltransferase; Corpus Striatum; Dextromethorphan; Dibenzocycloheptenes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Levorphanol; Male; Movement Disorders; Pyridines; Quinolinic Acid; Quinolinic Acids; Rats; Rats, Inbred Strains