Induction Of Ataxia Research Articles

The cannabinoid antagonist, AM251 attenuates ataxia related deficiencies in a cerebellar ataxic model

Aim: Disruption in cerebellar inputs, as well as dysfunction of Purkinje cells (PCs), causes a change in the timing of electrical signaling in the cerebellum resulting in disorders such as cerebellar ataxia. Although much clinical and molecular genetics research has been conducted to understand this disorder, there is no specific treatment for cerebellar ataxia. As cannabinoid type 1 receptors (CB1Rs) are highly expressed in the cerebellum and have been suggested as a therapeutic strategy, we determined whether AM251, a cannabinoid receptor antagonist, was neuroprotective of PCs in a rat cerebellar ataxic model.Materials and methods: To this end, we conducted behavioral and histological tests in the 3-acetylpyridine (3AP) rat cerebellar ataxia model, to explore whether AM251 was protective against induction of ataxia and cell death.Results: Rats with chemical degeneration of the inferior olive induced by 3AP (55 mg/kg, i.p.) clearly showed cerebellar ataxic symptoms. The locomotor activity and motor coordination of the ataxic animals were clearly disrupted compared to the control group. Further, histological analysis showed cell death and PCs degenerated with loss of cell membrane integrity associated with 3AP. Pre-treatment by AM251 improved the locomotor activity of the ataxic animals, and AM251 almost prevented PCs neuronal degeneration.Conclusion: Our data which show protection of cerebellar PCs and motor improvement in the ataxic rat model by treatment with AM251 suggests that targeting cannabinoid receptors should be considered for therapeutic intervention in cerebellar ataxia. HIGHLIGHTS: AM251 was protective against induction of ataxia and cell death. CBR antagonist typically ameliorated 3AP induced Ataxia. AM251 affected explorative and gait disturbances induced by 3AP. CBR antagonist improved impairments of anxiety-like behaviors following 3AP

Grafted human chorionic stem cells restore motor function and preclude cerebellar neurodegeneration in rat model of cerebellar ataxia.

Cerebellar ataxia (CA) is a form of ataxia that adversely affects the cerebellum. Cell replacement therapy (CRT) has been considered as a potential treatment for neurological disorders. In this report, we investigated the neuro-restorative effects of human chorionic stem cells (HCSCs) transplantation on rat model of CA induced by 3-acetylpyridine (3-AP). In this regard, HCSCs were isolated and phenotypically determined. Next, a single injection of 3-AP was administered for ataxia induction, and bilateral HCSCs implantation was conducted 3days after 3-AP injection, followed by expression analysis of a number of apoptotic, autophagic and inflammatory genes as well as vascular endothelial growth factor (VEGF) level, along with assessment of cerebellar neurodegeneration, motor coordination and muscle activity. The findings revealed that grafting of HCSCs in 3-AP model of ataxia decreased the expression levels of several inflammatory, autophagic and apoptotic genes and provoked the up-regulation of VEGF in the cerebellar region, prevented the degeneration of Purkinje cells caused by 3-AP toxicity and ameliorated motor coordination and muscle function. In conclusion, these data indicate in vivo efficacy of HCSCs in the reestablishment of motor skills and reversal of CA.

Mapping stimulation-induced beneficial and adverse effects in the subthalamic area of essential tremor patients

BackgroundStimulation of the subthalamic area (STA) is an effective treatment in essential tremor patients, but limited by stimulation induced adverse effects. The aim of this study was to determine the spatial distribution of stimulus related tremor suppression, ataxia induction and paresthesia of the upper limb in the subthalamic area (STA) of essential tremor patients. MethodsWe recruited eight patients with essential tremor in a stable postoperative condition (>3 months after surgery). Stimulation-induced effects were assessed with suprathreshold stimulation. Tremor severity was assessed with the Fahn-Tolosa-Marin tremor rating scale (TRS) and cerebellar impairment was evaluated using the international cooperative ataxia rating scale (ICARS). Patients rated paresthesia intensity with a visual analog scale. Linear regression analysis was performed to associate stereotactic coordinates with tremor, ataxia and paresthesia. ResultsSuprathreshold stimulation significantly decreased tremor and elicited ataxia and paresthesia in all patients (P < 0.001). Tremor rating scale (TRS) total score was positively correlated with y-coordinates (r = 0.44, P < 0.05), i.e. anterior stimulation sites were more effective to suppress tremor. Concerning adverse effects, ataxia induction was positively correlated with z-coordinates almost reaching statistical significance (r = 0.50, P = 0.07), i.e. inferior stimulation sites elicit stronger ataxia. Furthermore, paresthesia was positively correlated with y-coordinates (r = 0.66; P < 0.01) and to a lesser degree with x-coordinates (r = 0.32; P = 0.08), i.e. posterior and lateral stimulation sites within the STA caused more paresthesia. ConclusionAntero-dorso-medial stimulation site in the STA were associated with less tremor and adverse effects in our small single-center cohort of ET patients with thalamic DBS.

Evaluation of the spatial arrangement of Purkinje cells in ataxic rat's cerebellum after Sertoli cells transplantation.

Purkinje cells (PCs) pathology is important in cerebellar disorders like ataxia. The spatial arrangement of PCs after different treatments has not been studied extensively. Immunohistochemistry (IHC) analysis of cerebellum can give a proper tool for explaining the pathophysiology of PCs in ataxia. Here we stereologically analysed the 3-dimensional spatial arrangement of PCs in the cerebellum of rats after ataxia induction with 3-acetylpyridine (3-AP). Ataxia was induced in rats by intraperitoneal injection of 3-AP (65 mg/kg). Spatial arrangement of PCs for differences in ataxic rats with (3-AP-SC) or without (3-AP) Sertoli cells (SCs) transplantation was evaluated using second-order stereology. The IHC method by using antibodies to anti-calbindin in the cerebellum was applied. Our results showed that a random arrangement is at larger distances between PCs in 3-AP and 3-Ap-SC groups. Therefore the PCs are not normally arranged after 3-AP and SCs transplantation stored the spatial arrangements of the cells after ataxia induction in rats. IHC analyse shows that number of PCs was significantly improved after the SC transplantation. Segregation of PCs can be observed at some areas in the ataxic rats' cerebellum. However, the spatial arrangement of PCs was unchanged in SCs transplanted rats. (Folia Morphol 2018; 77, 2: 194-200).

P 73 Shorter pulse width reduces gait ataxia associated with VIM-DBS

Background Limb and gait ataxia following chronic VIM-DBS is a frequent and clinically relevant phenomenon ( Hwynn et al., 2011 ), which is likely caused by disruption of physiological cerebello-thalamic signaling and inadvertent cerebellar activation ( Reich et al., 2016 ). Ataxia dramatically improves after a pause of stimulation for more than 72 h. At the same time, tremor will reoccur, leaving the patient disabled. To date, no effective therapeutic option for stimulation-induced gait ataxia has been identified. Shorter pulse width than 60 μs have been suggested to broaden the therapeutic windows as fiber tracts involved in tremor suppression and induction of ataxia have differential electrophysiological properties ( Reich et al., 2015 , Groppa et al., 2014 ). Here, we explore the therapeutic value of 40 μs pulse width in treatment of stimulation-induced gait ataxia. Methods 5 patients received special access codes that allowed their neurostimulators to be programmed beyond regular limits. Spatiotemporal gait parameters were measured using an accelerometer-based kinematic motion analysis system (Mobility Lab, APDM). Measurements were repeated (1) ON best stimulation for tremor suppression (2) after 4 days of withdrawal of stimulation (3) after more than 6 weeks of adjusted stimulation with 40 μs pulse width. Clinical assessment of gait ataxia and tremor was done using Score for Assessment and Rating of Ataxia (SARA) items 1–3 and the Tremor-Rating-Score (TRS). Patients were asked to self-report their global impression of change (GIC-S). Results 4 of 5 patients self-reported an improvement of gait performance off stimulation and at DBS at short pulse width. Tremor scores were reduced with VIM-DBS similar for 40 μs (9.2 ± 3.8) and 60 μs (9.6 ± 4.0) pulse width compared to OFF DBS (21.4 ± 5.5; p = 0.065) and SARA axial items (1–3) decreased with stimulation OFF (2.8 ± 0.86) and 40 μs VIM-DBS (2.4 ± 0.74;) compared to 60 μs VIM-DBS (6.0 ± 0.89; p = 0.065). Coefficient of variability (CoV) of stride length and of shank range of motion were significantly reduced both OFF DBS and with 40 μs VIM-DBS (p Conclusions Our results add further evidence to the growing number of studies pointing to gait ataxia as a severe yet reversible side effect of thalamic stimulation rather than disease progression. Shorter pulsewidths may therefore be a promising approach to target stimulation-induced side effects while maintaining desired clinical efficacy of tremor suppression.

MTCL1 plays an essential role in maintaining Purkinje neuron axon initial segment.

The axon initial segment (AIS) is a specialized domain essential for neuronal function, the formation of which begins with localization of an ankyrin-G (AnkG) scaffold. However, the mechanism directing and maintaining AnkG localization is largely unknown. In this study, we demonstrate that invivo knockdown of microtubule cross-linking factor 1 (MTCL1) in cerebellar Purkinje cells causes loss of axonal polarity coupled with AnkG mislocalization. MTCL1 lacking MT-stabilizing activity failed to restore these defects, and stable MT bundles spanning the AIS were disorganized in knockdown cells. Interestingly, during early postnatal development, colocalization of MTCL1 with these stable MT bundles was observed prominently in the axon hillock and proximal axon. These results indicate that MTCL1-mediated formation of stable MT bundles is crucial for maintenance of AnkG localization. We also demonstrate that Mtcl1 gene disruption results in abnormal motor coordination with Purkinje cell degeneration, and provide evidence suggesting possible involvement of MTCL1 dysfunction in the pathogenesis of spinocerebellar ataxia.

Mechanisms of deep brain stimulation for essential tremor

Although essential tremor is often thought of as benign, it can be disabling to the point of justifying invasive deep brain stimulation (DBS). However, the mechanisms by which thalamic and subthalamic stimulation suppress tremor are poorly understood. In this issue of Brain , Groppa et al. (2014) quantified the performance of seven patients with essential tremor in a reaching task to determine the DBS target structures associated with therapeutic reduction in tremor and with the side effect of stimulation-induced ataxia. The optimum site of stimulation was usually in the posterior subthalamic area, beneath the inferior border of the thalamic nucleus ventralis intermedius. Probabilistic diffusion tractography identified the dentatothalamic tract as the key therapeutic DBS target structure. Supratherapeutic stimulation of this site produced upper limb ataxia, despite continued suppression of tremor. The authors systematically varied stimulation pulse strength and duration to find that stimulation chronaxies of 27 and 52 µs were associated with tremor suppression and the induction of ataxia, respectively. Chronaxie is loosely defined as the minimum duration at which a current twice threshold (minimum current with indefinitely long pulse duration) elicits a response and provides a clue as to the properties of the axons recruited. They reasoned that two different populations of large myelinated nerve fibres were affected: (i) dentatothalamic axons for the therapeutic effect; and (ii) afferent or efferent axons of the red nucleus for the stimulation-induced ataxia. However, the involvement of rubral pathways could not be confirmed with diffusion tractography. This work is an important contribution to a growing literature addressing the mechanisms of DBS and the preferred site of DBS stimulation for essential tremor. Ventralis intermedius has historically been the preferred stereotactic target for thalamotomy and DBS in the treatment of essential tremor and other tremor disorders (Miocinovic et al. , 2013), but recent postoperative correlations …

Physiological and anatomical decomposition of subthalamic neurostimulation effects in essential tremor

Postural tremor is the leading symptom in essential tremor, but in some cases intention tremor and limb ataxia emerge and can become highly disabling features. Deep brain stimulation of the thalamus or subthalamic white matter improve tremor and ataxia; however, the underlying network mechanisms are enigmatic. To elucidate the mechanisms of deep brain stimulation in essential tremor, we pursued a multimodal approach combining kinematic measures of reach-to-grasp movements, clinical assessments, physiological measures of neuronal excitability and probabilistic tractography from diffusion tensor imaging. Seven patients with essential tremor (age 62.9 ± 10.3 years, two females) received thalamic deep brain stimulation and a clinical examination of severity of limb tremor and ataxia at off stimulation, using therapeutic and supratherapeutic stimulation parameters. A reach-to-grasp task based on acoustic cues was also performed. To examine the electrical properties of target structures, we determined the chronaxie of neural elements modulated. A control group of 13 healthy subjects (age 56 ± 7.6 years, five females) underwent whole-brain diffusion tensor imaging at 3 T. Probabilistic tractography was applied in healthy subjects from seeds in cerebellum and midbrain to reconstruct the connectivity pattern of the subthalamic area. The positions of stimulation electrodes in patients were transferred into probability maps and connectivity values were correlated to clinical outcome measures. Therapeutic stimulation improved ataxia and tremor mainly during the target period of the reaching paradigm (63% reduction compared with off stimulation). Notably the acceleration (29%) and deceleration periods (41%) were improved. By contrast, supratherapeutic stimulation worsened ataxia during the deceleration period with a 55% increase of spatial variability, while maintaining near complete suppression of tremor. Chronaxie measures were in the range of rapidly-conducting myelinated fibres with significantly different values for the anti-tremor effect of therapeutic stimulation (27 s) and the pro-ataxic effect of supratherapeutic stimulation (52 s). The degree of connectivity to the dentato-thalamic tract at the stimulating electrode correlated significantly with the reduction of tremor in the therapeutic condition. Our data suggest that stimulation induced tremor reduction and induction of ataxia by supratherapeutic stimulation are mediated by different fibre systems. Probalistic tractography identified the dentato-thalamic tract as a likely target of tremor suppression. Stimulation-induced ataxia may be caused by additional recruitment of adjacent fibre systems at higher amplitudes. Stimulation with short pulse duration may help to increase the therapeutic window and focus on the anti-tremor effect.

The catalytic subunit of DNA-dependent protein kinase is downstream of ATM and feeds forward oxidative stress in the selenium-induced senescence response

Selenium induces a senescence response in cells through induction of ataxia–telangiectasia mutated (ATM) and reactive oxygen species (ROS). Although a role of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) in DNA double-strand break repair is established, it is unclear how these proteins function in response to selenium-induced oxidative stress and senescence induction. In this study, we demonstrated that pretreating normal human diploid fibroblasts with DNA-PK kinase inhibitor NU 7026 suppressed selenium-induced senescence response. Selenium treatment induced phosphorylation of DNA-PKcs on Thr-2647 and Ser-2056, the extent of which was decreased in the presence of ATM kinase inhibitor KU 55933 or the antioxidants N-acetylcysteine or 2,2,6,6-tetramethylpiperidine-1-oxyl. In contrast, the selenium-induced phosphorylation of ATM on Ser-1981 was not affected by NU 7026. Cells deficient in DNA-PKcs or pretreated with NU 7026 or N-acetylcysteine were defective in selenite-induced ROS formation. Taken together, these results indicate a distinct role of DNA-PKcs, in which this kinase can respond to and feed forward selenium-induced ROS formation and is placed downstream of ATM in the resultant senescence response.

Gait ataxia in essential tremor is differentially modulated by thalamic stimulation

Patients with advanced stages of essential tremor frequently exhibit tandem gait ataxia with impaired balance control and imprecise foot placement, resembling patients with a cerebellar deficit. Thalamic deep brain stimulation, a surgical therapy for otherwise intractable cases, has been shown to improve tremor, but its impact on cerebellar-like gait difficulties remains to be elucidated. Eleven patients affected by essential tremor (five females; age 69.8 ± 3.9 years; disease duration 24.4 ± 11.2 years; follow-up after surgery 24.7 ± 20.3 months) were evaluated during the following conditions: stimulation off, stimulation on and supra-therapeutic stimulation. Ten age-matched healthy controls served as the comparison group. Locomotion by patients and controls was assessed with (i) overground gait and tandem gait; (ii) balance-assisted treadmill tandem gait and (iii) unassisted treadmill gait. The two treadmill paradigms were kinematically analysed using a 3D opto-electronic motion analysis system. Established clinical and kinesiological measures of ataxia were computed. During stimulation off, the patients exhibited ataxia in all assessment paradigms, which improved during stimulation on and worsened again during supra-therapeutic stimulation. During over ground tandem gait, patients had more missteps and slower gait velocities during stimulation off and supra-therapeutic stimulation than during stimulation on. During balance-assisted tandem gait, stimulation on reduced the temporospatial variability in foot trajectories to nearly normal values, while highly variable (ataxic) foot trajectories were observed during stimulation off and supra-therapeutic stimulation. During unassisted treadmill gait, stimulation on improved gait stability compared with stimulation off and supra-therapeutic stimulation, as demonstrated by increased gait velocity and ankle rotation. These improvements in ataxia were not a function of reduced tremor in the lower limbs or torso. In conclusion, we demonstrate the impact of thalamic stimulation on gait ataxia in patients with essential tremor with improvement by stimulation on and deterioration by supra-therapeutic stimulation, despite continued control of tremor. Thus, cerebellar dysfunction in these patients can be differentially modulated with optimal versus supra-therapeutic stimulation. The cerebellar movement disorder of essential tremor is due to a typical cerebellar deficit, not to trembling extremities. We hypothesize that deep brain stimulation affects two major regulating circuits: the cortico-thalamo-cortical loop for tremor reduction and the cerebello-thalamo-cortical pathway for ataxia reduction (stimulation on) and ataxia induction (supra-therapeutic stimulation).

Co-treatment with riluzole, a neuroprotective drug, ameliorates the 3-acetylpyridine-induced neurotoxicity in cerebellar Purkinje neurones of rats: Behavioural and electrophysiological evidence

Riluzole has been shown to possess neuroprotective effects in a variety of neurological and animal model of diseases, including motor diseases. However, the mechanism(s) by which riluzole preserves the intrinsic electrophysiological characteristics of neuronal membrane has not been fully delineated. Ataxia is a clinical manifestation of disturbance in coordinated motor activity, which may be caused by cerebellar impairment. Here, the in vivo neuroprotective effect of riluzole on the intrinsic activity of Purkinje cells (PCs) in a rat model of cerebellar ataxia induced by 3-acetylpyridine (3-AP) was studied. Behavioural assessment tests, histological examination and whole cell patch clamp recording under current clamp conditions were used to explore the possible protective effect of riluzole against induction of ataxia with 3-AP treatment. Combined treatment with riluzole and 3-AP not only almost completely prevented the neuronal degeneration in cerebellar Purkinje cells layer but also the development of ataxia, which occurred following injection of 3-AP alone and partially improved the motor behaviour in comparison with ataxic rats. The normal firing behaviour and action potential characteristics of Purkinje neurones were preserved. The amplitude of both fast after hyperpolarization potential (fAHP) and post train after hyperpolarization potential, a marker of slow AHP (sAHP), along with the duration of post train AHP, which play an important role in regulating the firing behaviour were restored to the control conditions. These findings suggest that riluzole-induced neuroprotection may be mediated at least in part by activation of Ca 2+-dependent K + channel function.

786 Targeting of the Subthalamic Area Is Superior to the Ventrolateral Thalamus for Severe Intention Tremor, and Asymmetric Stimulation Can Prevent Side Effects

INTRODUCTION: Although deep brain stimulation (DBS) in the ventrolateral thalamus is an effective treatment for severe intention tremor, the optimal site for stimulation is the subject of ongoing debate. METHODS: DBS electrodes were implanted into one of five tracks explored by microrecording and microstimulation in seven patients with essential tremor and six patients with multiple sclerosis. Stereo-tactic coordinates of each electrode contact were determined from stereotactic x-rays, and the efficacy of each contact was assessed. RESULTS: Contacts located ventral to the intercommissural plane reduced lateralized Fahn scores by 63.6 ± 21.1% (right) and 67.9 ± 18.3% (left), whereas dorsal contacts were less effective (20.5 ± 16.4% and 17.6 ± 16.2%, respectively). Similarly, only stimulation below the intercommissural plane resulted in pronounced reduction of intention tremor assessed by magnetic tracking of grasping movements as well as accelerometer total power measuring high-amplitude batwing tremor. The mean coordinates of the most effective contacts (right: 12.9 ± 1.6, −7.4 ± 1.0, −1.6 ± 1.3; left: −12.3 ± 1.2, −7.3 ± 1.7, −2.6 ± 1.1; x, y, z in mm relative to the midcommissural point) suggested stimulation within the subthalamic area, which is corroborated by post hoc correlation with intraoperative microrecordings. Chronaxie values for suppression of tremor (27 ± 14 μs) and induction of ataxia (52 ± 15 μs; P < 0.05) suggested that tremor suppression is caused by modulation of large myelinated fibers. Notably, optimal contacts could not be used for permanent, bilateral stimulation in several instances, because this was associated with side effects, e.g., paresthesias or dysarthria. Whereas the optimal contact was generally chosen for the dominant side (left electrode), contralateral stimulation was performed with less effective contacts located more dorsally. CONCLUSION: For intention tremor, fiber tracks in the subthalamic area (zona incerta, prelemniscal radiation/cerebellothalamic projections, Forel H2) rather than neuronal cell bodies within the ventrolateral thalamus represent an effective target for DBS. Permanent, bilateral stimulation is frequently performed asymmetrically to prevent side effects.

Serotonin and pain: evidence that activation of 5-HT 1A receptors does not elicit antinociception against noxious thermal, mechanical and chemical stimuli in mice

In this study, we examined whether activation of 5-HT 1A receptors elicits antinociception in response to acute noxious chemical, thermal and mechanical stimuli in mice. In the writhing test, both agonists (e.g., 8-OH-DPAT, S 14671 and WY 50,324) and partial agonists (e.g., buspirone and gepirone) elicited a pronounced antinociception. However, antagonists (e.g., (−)-alprenolol and WAY 100,135) also induced antinociception and, at lower (inactive) doses, failed to modify the action of agonists. In addition, the separation between doses required for induction of antinociception as compared to those required for induction of ataxia (in the rotarod test) was variable and low for both agonists (median: 1.9) and partial agonists (median: 1.3), although it was somewhat greater for antagonists (≳ 3.3). In the hot-plate test, only certain agonists (e.g., 8-OH-DPAT) and partial agonists (e.g., gepirone) elicited antinociception and their actions were not attenuated by 5-HT 1A antagonists which, themselves, were inactive in this paradigm. The 5-HT 1C/2 antagonist, ritanserin, the 5-HT 3 antagonist, ondansetron, the dopamine D 2 receptor antagonist, raclopride, and the α 1-adrenoceptor antagonist, prazosin, were also ineffective in modifying the antinociception evoked by 5-HT 1A agonists and partial agonists in the hot-plate test. In contrast, their actions were strongly attenuated by the α 2-adrenoceptor antagonist, idazoxan. In the tail-flick tests to noxious heat and noxious pressure, 5-HT 1A receptor agonists, partial agonists and antagonists generally failed to induce antinociception. Moreover, modulation of stimulus intensity (from very weak to very intense) did not reveal any influence upon the latency to respond. In conclusion, in the writhing test, the data provide no evidence for a specific antinociceptive effect of the activation of 5-HT 1A receptors. Further, in the hot-plate test, for those 5-HT 1A agonists and partial agonists which induce antinociception, α 2-adrenoceptors rather than 5-HT 1A receptors are implicated in their actions. Finally, in reflexive tests, irrespective of stimulus quality or intensity, 5-HT 1A agonists and partial agonists do not mediate antinociception. These data suggest that the activation of 5-HT 1A receptors does not, under these conditions of acute noxious stimulation, elicit antinociception.

The glycine B receptor partial agonist, (+)-HA 966, enhances induction of antinociception by RP 67580 and CP-99,994

The tachykinin receptor antagonists (3aR, 7aR)-7,7-diphenyl-2(1-imino-2-(2-methoxyphenylethyl)perhydroisoindole) (RP 67580) and (+)-(2 S−3 S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994), which act selectively at neurokinin (NK) 1 receptors, inhibited the early phase of formalin-induced pain in mice. Although (+)-(1-hydroxy-3-aminopyrrolidine-2-one) ((+)-HA 966), a partial agonist at glycine B receptors, was inactive alone,it potentiated the actions of RP 67580 (but not its inactive stereoisomer, RP 68651) and CP-99,994. In its presence, the dose-response curve for RP 67580 was dose-dependently shifted to the left. In contrast, (+)-HA 966 did not modify the induction of ataxia by RP 67580 and CP-99,994. These data suggest that co-administration of partial agonists at glycine B receptors may improve the antinociceptive potency and ‘therapeutic window’ of tachykinin NK 1 receptor antagonists.

Stereotyped behavior correlates better than ataxia with phencyclidine-receptor interactions

The interaction of phencyclidine, dexoxadrol, their analogs and stereoisomers with phencyclidine receptors was compared to their ability to induce stereotyped behavior and ataxia after i.c.v. administration of rats. The order of potency for binding to phencyclidine receptors revealed that among the stereoisomers of phencyclidine derivatives, the (+) isomer was more potent that the (-) isomer. A similar order of potency of phencyclidine derivatives and degree of stereoselectivity was seen in the assays for stereotyped behavior and phencyclidine receptor interactions, which resulted in a good correlation between the relative potencies for binding to phencyclidine receptors and inducing stereotyped behavior. However, the order of potency for induction of ataxia and the stereoselectivity was different than that seen in the assays for phencyclidine receptor interactions and stereotyped behavior. A comparison of relative potencies for binding to phencyclidine receptors to induction of ataxia still resulted in a good fit to a straight line, but the line did not intersect the origin, indicating that a non-phencyclidine receptor component is also involved in mediating ataxia. Dextrorphan and 2-methyl-3,3-diphenyl-3-propylamine were equipotent as phencyclidine in phencyclidine receptor and behavioral assays. The order of potency for interacting with phencyclidine recetors and inducing phencyclidine-like behavior by the isomers of cyclazocine were opposite to that of other phencyclidine analogs. Also, the order of potency for induction of ataxia by the isomers of N-allylnormetazocine was opposite to that for phencyclidine receptor interactions. Ethylketocyclazocine did not induce any stereotyped behavior or ataxia, indicating that it is unlikely that a κ opioid receptor interaction plays a role in mediating ataxia. Furthermore, stereotyped behavior and ataxia were not due to interactions with μ, κ or δ opioid receptors as naloxone did not antagonize the behavioral effects of phencyclidine, (-)cyclazocine or (-)N-allylnormetazocine. These results indicate that stereotyped behavior is mediated by phencyclidine receptors, whereas ataxia is mediated by more than just phencyclidine receptors.

Differential antagonism of denzimol to various components of metrazol-induced seizures in rats and mice

The antagonism of various components of maximal. metrazol-seizures and the induction of ataxia have been studied in mice and rats by comparing Denzimol to 10 standard antiepileptic drugs. The data were analyzed by Cluster and Principal Components Analysis. Denzimol, phenytoin, carbamazepine and AD-810 showed an antagonistic effect on tonic but not on clonic seizures regardless of the animal species. Barbiturates, benzodiazepines and valproic acid, on the other hand, antagonized the whole pattern of metrazol-seizures. The selective activity of Denzimol and phenytoin against tonic seizures was also confirmed from literature data, which reported the activity of these compounds against bicuculline, thiosemicarbazide or picrotoxin induced convulsions.