The mouse beam walking assay offers improved sensitivity over the mouse RotaRod in determining motor coordination deficits induced by benzodiazepines

Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Harlow, UK.
Journal of Psychopharmacology (Impact Factor: 2.81). 06/2005; 19(3):221-7. DOI: 10.1177/0269881105051524
Source: PubMed

ABSTRACT The mouse rotarod test of motor coordination/sedation is commonly used to predict clinical sedation caused by novel drugs. However, past experience suggests that it lacks the desired degree of sensitivity to be predictive of effects in humans. For example, the benzodiazepine, bretazenil, showed little impairment of mouse rotarod performance, but marked sedation in humans. The aim of the present study was to assess whether the mouse beam walking assay demonstrates: (i) an increased sensitivity over the rotarod and (ii) an increased ability to predict clinically sedative doses of benzodiazepines. The study compared the effects of the full benzodiazepine agonists, diazepam and lorazepam, and the partial agonist, bretazenil, on the mouse rotarod and beam walking assays. Diazepam and lorazepam significantly impaired rotarod performance, although relatively high GABA-A receptor occupancy was required (72% and 93%, respectively), whereas beam walking performance was significantly affected at approximately 30% receptor occupancy. Bretazenil produced significant deficits at 90% and 53% receptor occupancy on the rotarod and beam walking assays, respectively. The results suggest that the mouse beam walking assay is a more sensitive tool for determining benzodiazepine-induced motor coordination deficits than the rotarod. Furthermore, the GABA-A receptor occupancy values at which significant deficits were determined in the beam walking assay are comparable with those observed in clinical positron emission tomography studies using sedative doses of benzodiazepines. These data suggest that the beam walking assay may be able to more accurately predict the clinically sedative doses of novel benzodiazepine-like drugs.

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    • "However, constant testing environments such as testing within the animal's cage are necessary in order to retrieve reliable and valid data in the adhesive removal test (Schallert and Woodlee, 2005), as should be the case for any other behavioral test as well. Similar findings were found regarding the balance beam test, which was more sensitive in assessment of motor coordination deficits than the rota rod test, albeit these tests were performed in a non-stroke model (Stanley et al., 2005). On the contrary, the pole test cannot be recommended for conditions of severe stroke since some animals are not able to perform the test at all due to the strenuous nature of the task, as has been discussed afore regarding the tight rope test. "
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    ABSTRACT: Systemic transplantation of neural progenitor cells (NPCs) in rodents reduces functional impairment after cerebral ischemia. In light of upcoming stroke trials regarding safety and feasibility of NPC transplantation, experimental studies have to successfully analyze the extent of NPC-induced neurorestoration on the functional level. However, appropriate behavioral tests for analysis of post-stroke motor coordination deficits and cognitive impairment after NPC grafting are not fully established. We therefore exposed male C57BL6 mice to either 45 min (mild) or 90 min (severe) of cerebral ischemia, using the thread occlusion model followed by intravenous injection of PBS or NPCs 6 h post-stroke with an observation period of three months. Post-stroke motor coordination was assessed by means of the rota rod, tight rope, corner turn, inclined plane, grip strength, foot fault, adhesive removal, pole test and balance beam test, whereas cognitive impairment was analyzed using the water maze, the open field and the passive avoidance test. Significant motor coordination differences after both mild and severe cerebral ischemia in favor of NPC-treated mice were observed for each motor coordination test except for the inclined plane and the grip strength test, which only showed significant differences after severe cerebral ischemia. Cognitive impairment after mild cerebral ischemia was successfully assessed using the water maze test, the open field and the passive avoidance test. On the contrary, the water maze test was not suitable in the severe cerebral ischemia paradigm, as it too much depends on motor coordination capabilities of test mice. In terms of both reliability and cost-effectiveness considerations, we thus recommend the corner turn, foot fault, balance beam, and open field test, which do not depend on durations of cerebral ischemia.
    Frontiers in Cellular Neuroscience 10/2014; 8:338. DOI:10.3389/fncel.2014.00338 · 4.18 Impact Factor
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    • "The method previously described by Stanley et al. (2005) was used for this study with modifications. Briefly, each mouse was trained to walk from a start platform along a ruler (80 cm long, 3 cm wide) elevated 30 cm above the bench by metal support to a goal box (enclosed hamster house). "
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    ABSTRACT: Decoctions of Ficus platyphylla Del.-Holl (Family: Moraceae) are used in the Nigeria's folk medicine for the management of epilepsy and their efficacies are widely acclaimed among the rural communities of northern Nigeria. To examine the behavioral and anticonvulsant properties of the standardized methanol extract of Ficus platyphylla (FP) stem bark, in order to scientifically describe its potential values in the management of convulsive disorders. The High performance liquid chromatography (HPLC) and preliminary phytochemical analysis of the methanol extract were evaluated and the intraperitoneal median lethal dose (LD50) determined in mice. Effects of FP were investigated on some murine models of behavior and its anticonvulsant effects studied on pentylenetetrazole (PTZ)-, strychnine (STN)-, picrotoxin (PCT)-, isoniazid (INH)-, aminophylline (AMI) and maximal electroshock (MES) seizures in mice. The intraperitoneal oral LD50 of FP was estimated to be 5000mg/kg. FP significantly reduced the locomotor activities including the total distance covered, speed, active time and rearing counts. It shortened the onset and prolonged the duration of diazepam induced sleep, but had no effect on motor coordination on the rota-rod treadmill or beam-walking assay in mice at the doses tested. The extract protected the mice against PTZ and STN-induced seizures and significantly delayed the latencies of myoclonic jerks and tonic seizures induced by all the standard convulsant agents (PTZ, PCT, INH, STN and AMI) used in this study, but failed to protect the mice against MES seizures at doses tested. The HPLC fingerprint of the extract shows a spectrum profile characteristic of Ficus platyphylla, while the preliminary phytochemical screening revealed the presence of saponins, flavonoids and tannins. Our study provides scientific evidence that FP may contain psychoactive principles with potential anticonvulsant properties, thus supporting further development of the psychoactive components of this plant as anticonvulsant agents.
    Journal of ethnopharmacology 04/2014; 154(2). DOI:10.1016/j.jep.2014.03.061 · 2.94 Impact Factor
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    • "Animals were allowed a maximum of 60 s to cross. Time to cross and number of foot faults (ff; one or both hind limbs slip from beam) were counted for each crossing attempt, and this was repeated at post-injury d 1, 3, and 7 [18] "
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    ABSTRACT: Pharmacologic therapy for traumatic brain injury (TBI) has remained relatively unchanged for decades. Ghrelin, an endogenously produced peptide, has been shown to prevent apoptosis and blood-brain barrier dysfunction after TBI. We hypothesize that ghrelin treatment will prevent neuronal degeneration and improve motor coordination after TBI. A weight drop model created severe TBI in three groups of BALB/c mice: Sham, TBI, and TBI + ghrelin (20 μg intraperitoneal ghrelin). Brain tissue was examined by hematoxylin and eosin and Fluoro-Jade B (FJB) staining to evaluate histologic signs of injury, cortical volume loss, and neuronal degeneration. Additionally, motor coordination was assessed. Ghrelin treatment prevented volume loss after TBI (19.4 ± 9.8 mm(3)versus 71.4 ± 31.4 mm(3); P < 0.05). Similarly, although TBI increased FJB-positive neuronal degeneration, ghrelin treatment decreased FJB staining in TBI resulting in immunohistologic patterns similar to sham. Compared with sham, TBI animals had a significant increase in foot faults at d 1, 3, and 7 (2.75 ± 0.42; 2.67 ± 0.94; 3.33 ± 0.69 versus 0.0 ± 0.0; 0.17 ± 0.19; 0.0 ± 0.0; P < 0.001). TBI + ghrelin animals had significantly decreased foot faults compared with TBI at d 1, 3, and 7 (0.42 ± 0.63; 0.5 ± 0.43; 1.33 ± 0.58; P versus TBI <0.001; P versus sham = NS). Ghrelin treatment prevented post-TBI cortical volume loss and neurodegeneration. Furthermore, ghrelin improved post-TBI motor deficits. The mechanisms of these effects are unclear; however, a combination of the anti-apoptotic and inflammatory modulatory effects of ghrelin may play a role. Further studies delineating the mechanism of these observed effects are warranted.
    Journal of Surgical Research 10/2013; DOI:10.1016/j.jss.2013.09.030 · 2.12 Impact Factor
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