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PubMed2005

Impaired long-term habituation is dissociated from increased locomotor activity after sensorimotor cortex compression.

Behavioural habituation to a novel environment is a simple form of learning in rodents. We studied the habituation and locomotor activity (LMA) of Wistar rats subjected to unilateral, transient (30min) extradural compression (EC) of the right sensorimotor cortex. One group of rats was tested every 24h during the first 5 days (D1-D5) post-EC. Two other groups were tested for the first time in the LMA boxes on D3 and D6 post-EC and their performance was compared with the group tested on D1 (activity in a novel environment). Total and center locomotion, vertical activity and time spent in the center of the LMA box were reduced on D1 post-EC and normalized by D2. The EC-induced motor paresis was undetectable on the rotarod by D2 and on the beam-walking by D3. Total locomotion, vertical activity and time spent in the center of EC-rats significantly increased from D1 to D3. EC caused neurodegeneration in the cortex, caudate putamen and thalamus as detected by Fluoro-Jade staining. The size of the cortical damage decreased from D2 to D5 in the medial and caudal regions of the compressed hemisphere, in accordance with recovery of motor function. LMA provided additional information in the follow-up of recovery from brain injury and habituation to the environment. Thus, long-term, inter-session habituation was impaired from D1 to D3 but dissociated from increased LMA intra-session on D3, when the motor deficits provoked by EC were already undetectable in the rotarod and beam-walking tests.

Analysis of Variance↗
PubMed2005

The use of behavioral test batteries, II: effect of test interval.

Test batteries are commonly used to assess the behavioral phenotype of genetically modified and inbred strains of mice. However, few systematic studies have been employed to address several key issues concerning the use of a test battery. The current study was designed to address whether inter-test interval affects behavioral performance. Male mice of 3 different inbred strains and one F1 hybrid strain were randomly assigned to either a test battery with 1 week inter-test intervals, or a rapid test battery with 1-2 day inter-test intervals. The test battery included a neurological exam, open-field activity, light-dark exploration, rotarod test, prepulse inhibition, and startle habituation. The experiment was repeated with female animals of 2 different strains. As expected, there were strain differences on each of the behavioral assays; however, there was no major difference in performance between mice of the standard test battery and the rapid test battery. Similar results were found with females. These results indicate that the interval between most tests could be as little as 1-2 days, with little significant effect on overall performance. Thus, it is possible with the current test battery to reduce the inter-test interval to facilitate the rate of studying and identifying behavioral phenotypes in mice.

Analysis of Variance↗
PubMed2006

Differences in behavioural test battery performance between mice with hippocampal and cerebellar lesions.

Effects of hippocampal or cerebellar lesions have been described extensively, but the ability of behavioural tests for laboratory mice to distinguish between such lesions has not been studied in detail. We compared the behavioural consequences of large bilateral hippocampal and hemispheric cerebellar lesions with eight commonly used tests that included elements of neuromotor performance, exploratory behaviour, and learning and memory ability. Dissociation between the effects of the different lesions was most obviously demonstrated by neuromotor impairment in cerebellum-lesioned mice (typically in the rotarod task) and hyperactivity in hippocampus-lesioned mice (typically in cage activity recordings). Several of the behavioural variables derived from the test battery correlated differently with the size of the hippocampal and cerebellar lesions. In contrast, no absolute dissociation between the effects of these lesions was found in the Morris maze, a reportedly hippocampus-dependent learning and memory task. The contextual fear conditioning task, on the other hand, did reveal a selective decrease of context-dependent freezing in hippocampus-lesioned mice, whereas cerebellum-lesioned animals displayed an increase in freezing responses. By and large, the present battery of tests does allow differentiation between the effects of cerebellar and hippocampal lesions in laboratory mice.

Animals↗
PubMed2005

A preclinical comparison between different opioids: antinociceptive versus adverse effects.

Reduced side-effect liability of opioids may enhance the patient's quality of life and decrease the incidence of opioid-insensitive pain. Literature offers few comparative data between different opioids at equianalgesic doses. Therefore morphine, fentanyl, buprenorphine, codeine, hydrocodone and oxycodone were compared for analgesic properties and side-effect profiles in rats. Analgesic efficacy was analysed using a tail withdrawal test for acute thermal nociception, a formalin test for chemically induced inflammatory pain and a von Frey test for mechanical hypersensitivity. For side-effect profiling inhibition of gastrointestinal activity was evaluated in a charcoal and ricinus oil test, arterial PCO(2) was determined for measuring respiratory depression, the discriminative stimulus properties linked to the narcotic cue were assessed using a drug discrimination learning test, and motor coordination was tested through rotarod performance. ED(50)'s for the occurrence of side-effects were compared to ED(50)'s in behavioural pain tests. Fentanyl had a strong analgesic potency and, compared to other opioids, an acceptable side-effect profiling at analgesic ED(50)'s. Also consistent was the ceiling effect of buprenorphine implying an increased safety margin for side-effects, but a decreased analgesic efficacy. Differences between opioids as observed in this study can have important indications for their use in acute as well as in the onset of chronic treatments.

Analgesics↗
PubMed2001

Cholecystokinin2 receptor-deficient mice display altered function of brain dopaminergic system.

RATIONALE: Cholecystokinin (CCK) has been shown to coexist and interact with dopamine in the regulation of behaviour. Two different CCK receptors (CCK1 and CCK2) have an opposite influence on the activity of dopamine neurons. Stimulation of CCK2 receptors decreases the release of dopamine and that receptor could mediate the neuroleptic-like effect of CCK. OBJECTIVE: To investigate the activity of the dopaminergic system in pharmacological experiments on CCK2 receptor (CCK2R)-deficient mice. METHODS: We used age- and sex-matched littermates in all our experiments. To evaluate the behavioural differences, we performed the rotarod test and measured the locomotor activity of animals using computer-connected photoelectric motility boxes. Amphetamine and apomorphine, two dopaminergic drugs with different pharmacodynamic properties, were used to influence the activity of the dopaminergic system in the brain. Neurochemical differences related to the different genotype were analysed by means of high-performance liquid chromatography and radioligand binding studies. RESULTS: Motor co-ordination was significantly impaired in the rotarod test of CCK2R receptor-deficient mice. Moreover, the locomotor activity of heterozygous (+/-) and homozygous (-/-) CCK2R receptor-deficient mice was somewhat reduced. A low dose of apomorphine (0.1 mg/kg), an unselective agonist of dopamine receptors, suppressed locomotor activity significantly more in homozygous (-/-) and heterozygous (+/-) mutant mice than in their wild-type (+/+) littermates. Amphetamine (3-6 mg/kg), increasing release of dopamine from the presynaptic terminals, caused a dose-dependent motor stimulation in wild-type (+/+) mice. In heterozygous (+/-) and homozygous (-/-) mice, a lower dose of amphetamine (3 mg/kg) did not alter the locomotor activity, whereas the higher dose of (6 mg/kg) induced a significantly stronger increase in locomotor activity in homozygous (-/-) mice than in their heterozygous (+/-) and wild-type (+/+) littermates. Despite the changes in the action of apomorphine and amphetamine in homozygous (-/-) mice, we did not find any significant differences in the concentration of dopamine and their metabolites in the striatum or cortex. However, the density of dopamine D2 receptors was significantly increased in the striatum of homozygous (-/-) animals compared with wild-type (+/+) mice. CONCLUSIONS: The targeted mutation of the CCK2 receptor gene induced gene dose-dependent changes in the activity of the dopaminergic system. The sensitivity of presynaptic dopamine receptors was increased in heterozygous (+/-) and homozygous (-/-) animals, whereas the increase in sensitivity of postsynaptic dopamine receptors was apparent only in homozygous (-/-) mice.

Animals↗
PubMed2007

Mouse inbred strain differences in ethanol drinking to intoxication.

Recently, we described a simple procedure, Drinking in the Dark (DID), in which C57BL/6J mice self-administer ethanol to a blood ethanol concentration (BEC) above 1 mg/ml. The test consists of replacing the water with 20% ethanol in the home cage for 4 h early during the dark phase of the light/dark cycle. Three experiments were conducted to explore this high ethanol drinking model further. In experiment 1, a microanalysis of C57BL/6J behavior showed that the pattern of ethanol drinking was different from routine water intake. In experiment 2, drinking impaired performance of C57BL/6J on the accelerating rotarod and balance beam. In experiment 3, 12 inbred strains were screened to estimate genetic influences on DID and correlations with other traits. Large, reliable differences in intake and BEC were detected among the strains, with C57BL/6J showing the highest values. Strain means were positively correlated with intake and BEC in the standard (24 h) and a limited (4 h) two-bottle ethanol vs. water test, but BECs reached higher levels for DID. Strain mean correlations with other traits in the Mouse Phenome Project database supported previously reported genetic relationships of high ethanol drinking with low chronic ethanol withdrawal severity and low ethanol-conditioned taste aversion. We extend these findings by showing that the correlation estimates remain relatively unchanged even after correcting for phylogenetic relatedness among the strains, thus relaxing the assumption that the strain means are statistically independent. We discuss applications of the model for finding genes that predispose pharmacologically significant drinking in mice.

Alcohol Drinking↗
PubMed2004

Postnatal caffeine exposure: effects on motor skills and locomotor activity during ontogenesis.

It has been shown that long-term postnatal caffeine treatment results in biochemical and behavioral changes persisting into adulthood. The effects of postnatal chronic exposure to this methylxanthine on motor skills and locomotor activity were studied with a battery of motor and behavioral tests (negative geotaxis test, wire mesh ascending test, jumping down with a choice test, bar holding test, rotarod test and open field test) in rats during development. Pup rats were daily injected with caffeine (10 mg/kg or 20 mg/kg, s.c.) during postnatal days 7-11 (the P7 group) and/or 13-17 (the P13 group). Motor impairments occurred in 15-, 18- and 21-day-old rats treated with caffeine at P7-P11, whereas, pups exposed to caffeine from P13 to P17 exhibited worse performance only in the bar holding test at the age of 18 days. The P7 group was hyperactive in an open field during the whole period of testing. In contrast, the P13 group showed a decrease of motor activity at postnatal days 25 and 32. In conclusion, postnatal treatment of rats with caffeine leads to impairments of motor skills and changes in locomotor activity. The results are dependent at the developmental stages at caffeine administration as well as at age when tests are performed.

Age Factors↗
PubMed2005

A new model of reversible sinus sagittalis superior thrombosis in the rat: magnetic resonance imaging changes.

OBJECTIVE: The causes of cerebral sinus and vein occlusion and the accompanying parenchymal changes remain largely unexplained. The clinical variability and low incidence of the disease complicate systematic clinical investigations. Animal studies are indispensable; however, existing animal models of sinus thrombosis do not allow for long-term follow-up studies and are not suitable for pharmacological recanalization because sinus thrombosis is induced by ligation and injection of thrombogenic substances and does not resemble sinus thrombosis in humans. METHODS: We induced thrombosis of the superior sagittal sinus (SSS) by careful topical application of ferric chloride onto the SSS of rats, leading to highly reproducible occlusions. Magnetic resonance imaging was performed immediately after initiation of thrombosis and on postoperative Days 1, 2, and 7. Diffusion- and T2-weighted images allowed for calculation of the apparent diffusion coefficient and T2 relaxation time. Vascular status was assessed by venous magnetic resonance angiography. Neurological deficits were assessed with the rotarod test. RESULTS: Seven days after induction of thrombosis, partial recanalization (50.7% of the SSS remaining occluded) was accompanied by a resolution of early generalized changes of the apparent diffusion coefficient and of T2 relaxation time, indicating edema of the entire brain parenchyma. Compared with sham-treated animals, clinical skills in the experimental group improved over time, which was statistically independent from the degree of recanalization. Histopathological analysis revealed no signs of cerebral infarction. CONCLUSION: This is the first animal model of SSS thrombosis that offers the possibility to investigate pathophysiological aspects of the disease as well as the influence of therapy on the nature of disease progression.

Animals↗
PubMed2005

The pre-ischaemic neuroprotective effects of N1-dansyl-spermine in a transient focal cerebral ischaemia model in mice.

The pre-ischaemic neuroprotective potential of a novel polyamine/NMDA antagonist N1-dansyl-spermine (1-5 mg kg(-1)) was studied in a transient focal cerebral ischaemia model in mice in comparison to a reference compound, MK-801 (1 or 3 mg kg(-1)). The intraluminal suture transient middle cerebral artery occlusion (MCAO) model was used. N1-dansyl-spermine and MK-801 were administered (i.p.) 30 min prior to ischaemia. A range of histological and behavioural assessments was employed. N1-dansyl-spermine had a comparable effect to MK-801 at reducing the percentage hemisphere lesion volume (%HLV) at the doses tested. Furthermore, N1-dansyl-spermine reduced the ischaemic brain oedema, which MK-801 did not. N1-dansyl-spermine significantly reversed the decrease of locomotor activity (LMA) caused by the MCAO and showed a significant effect at improving the rotarod performance impaired by MCAO. In contrast, MK-801 had no beneficial effect on sensorimotor function and even worsened the LMA. These results clearly demonstrate the pre-ischaemic neuroprotective effect of N1-dansyl-spermine in a transient focal cerebral ischaemia model.

Animals↗
PubMed2006

Design and synthesis of anticonvulsants from a combined phthalimide-GABA-anilide and hydrazone pharmacophore.

Two series of pharmacophoric hybrids of phthalimide-GABA-anilides/hydrazones were designed and synthesized and evaluated for their anticonvulsant and neurotoxic properties. The structures of the synthesized compounds were confirmed by the use of their spectral data besides elemental analysis. Initial anticonvulsant screening was performed using intraperitoneal (i.p.) maximal electroshock-induced seizure (MES), subcutaneous pentylenetetrazole (scPTZ), subcutaneous strychnine (scSTY), and intraperitoneal picrotoxin (ipPIC)-induced seizure threshold tests. All of the compounds were ineffective in the MES test. Most of the compounds were found to be effective in the scSTY and ipPIC models and very few compounds showed protection in the scPTZ model.

Anilides↗
PubMed2005

Stimulus complexity dependent memory impairment and changes in motor performance after deletion of the neuronal gap junction protein connexin36 in mice.

Gap junction channels, composed of connexin (Cx) proteins, are conduits for intercellular communication and metabolic exchange in the central nervous system. Connexin36 (Cx36) is expressed in distinct subpopulations of neurons throughout the mammalian brain. Deletion of the Cx36 gene in the mouse affected power and frequency of gamma and sharp wave-ripple oscillations, putative correlates of memory engram inscription. Here, we present a behavioral analysis of Cx36-deficient mice. Activity patterns, exploratory- and anxiety-related responses were largely unaffected by elimination of Cx36, while sensorimotor capacities and learning and memory processes were impaired. Repeated testing on the rotarod suggested that the Cx36-deficient mice showed slower motor-coordination learning. After a retention interval of 24 h the Cx36-deficient mice showed habituation to an open-field, but failed to habituate to a more complex spatial environment (Y-maze). A more pronounced memory impairment was found when Cx36 knockout mice had to remember recently explored objects. Cx36-deficient mice were unable to recognize objects after short delays of 15 and 45 min. These data suggest that lack of Cx36 induces memory impairments that vary in dependence of the complexity of the stimuli presented. Our results suggest that neuronal gap junctions incorporating Cx36 play a role in learning and memory.

Analysis of Variance↗
PubMed2006

Dissociation between vasospasm and functional improvement in a murine model of subarachnoid hemorrhage.

OBJECT: The efficacy of nimodipine was examined in a murine model of subarachnoid hemorrhage (SAH). End points included the diameter of the lumen of the middle cerebral artery (MCA) and behavioral outcome. An apolipoprotein E (apoE)-mimetic peptide, acetyl-AS-Aib-LRKL-Aib-KRLL-amide, previously shown to have promise in this model was tested both alone and in combination with nimodipine. The effects of carboxyamidotriazole (CAI), a non-voltage-gated calcium channel blocker, were explored using the same animal paradigm. METHODS: Experimental SAH was induced in male C57B1/6J mice. For 3 days postoperatively, behavioral analyses were performed. In the first experiment, the mice were treated with vehicle or with low- or high-dose CAI for 3 days. In the second experiment, the mice were treated with vehicle, high- and low-dose nimodipine, and/or the apoE-mimetic peptide. On postoperative Day 3 each mouse was killed and perfused. Following this, the right MCA was removed and its lumen measured. Mice that received nimodipine demonstrated significant behavioral improvements when compared with vehicle-treated mice, but there was no clear dose-dependent effect on MCA diameter. Administration of the apoE-mimetic peptide was associated with improved functional performance and a significant reduction in vasospasm. Mice that received high-dose CAI performed worse on functional tests, despite a significant increase in the diameters of their MCA lumina. CONCLUSIONS: These results demonstrate a dissociation between vasospasm and neurological outcomes that is consistent with findings of previous clinical trials.

Animals↗
PubMed2006

Behaviour changes in a transgenic model of Huntington's disease.

Huntington's disease is an autosomal dominant inherited disorder, caused by an expanded polyglutamine region of a protein called huntingtin with unknown function. Transgenic mice expressing the N-terminal of huntingtin, containing 82 glutamines, exhibit a progressive disorder, which resembles to the human disease. In this study, we tested the longitudinal behaviour changes in this transgenic line in open-field and elevated-plus-maze tests. The motor performance deteriorated at 12 weeks of age and the disease progressed as indicated by the decreased total distance covered, the decreased mean velocity and the decreased exploratory behaviour. The level of anxiety was unchanged in transgenic mice as compared with their littermate controls. The motor deterioration was similar to that in other Huntington's disease models, while the level of anxiety was different. These tests are suitable means of following the progression of the disease and useful for studies of the effects of therapeutic interventions.

Animals↗
PubMed2006

Preclinical evaluation of 2,2,3,3-tetramethylcyclopropanecarbonyl-urea, a novel, second generation to valproic acid, antiepileptic drug.

2,2,3,3-Tetramethylcyclopropanecarbonylurea (TMCU) is an amide derivative of a tetramethylcyclopropyl analogue of valproic acid (VPA), one of the leading antiepileptic drugs. Structural considerations used in the design of TMCU aimed to enhance the anticonvulsant potency of VPA and to prevent its two life-threatening side effects; i.e., teratogenicity and hepatotoxicity. The anticonvulsant activity of TMCU was evaluated in the MES, scMet, 6-Hz, scBic and scPic tests, and also in the hippocampal kindling model of partial seizures and lamotrigine-resistant amygdala kindling model of therapy-resistant seizures. Minimal motor impairment was determined using the rotorod test in mice and the positional sense test, muscle tone test, and gait and stance test in rats. The antinociceptive effect of TMCU was evaluated in the mouse formalin model of acute-tonic pain. The molecular mechanisms of action of TMCU were investigated in electrophysiological studies using the whole-cell patch-clamp technique. Teratogenicity studies were performed in a SWV/Fnn-mouse model of VPA-induced teratogenicity. TMCU hepatotoxicity was evaluated following 1-week intraperitoneal and oral administration of 50, 250 and 500 mg/kg doses to rats. In the hepatotoxicity study the blood levels of TMCU were evaluated at day 1 and day 7 of the treatment. TMCU mutagenicity was evaluated in the Ames test.

Analysis of Variance↗
PubMed2004

Impaired motor coordination on static rods in BSE-infected mice.

Scrapie and bovine spongiform encephalopathy (BSE) are both progressive neurodegenerative diseases that are transmissible to mice. The onset of clinical symptoms is more subtle and variable in murine BSE than in murine scrapie. Assessment of behavioural changes that occur throughout disease would aid early diagnosis of disease so that more consistent end points could be made and potential therapies could be investigated. C57BL/6J mice inoculated via the intraperitoneal route with 301C BSE or control inoculum were monitored on a fortnightly basis. The end point was when a mouse showed clinical signs as opposed to behavioural signs of BSE for two consecutive observations. Significant loss of motor function, as assessed by mice balancing on a static rod, was observed consistently from approximately 40 days prior to death. No significant differences in home cage activity (locomotion, rearing) or cognitive function (T-maze alternation) were observed. However, there was an increase in digging by BSE-infected mice from an early stage. This data will aid the standardisation of behavioural tests to characterise and assess the onset of BSE.

Analysis of Variance↗
PubMedDate not supplied

Bupropion-induced convulsions: preclinical evaluation of antiepileptic drugs.

Bupropion, a unique, non-nicotine smoking cessation aid and an effective antidepressant, is well known to produce seizures following overdosing in humans. However, the experimental background for the usefulness of antiepileptic drugs in the protection against bupropion-induced convulsions has not been established yet. Therefore, we tested if the antiepileptic drugs were able to protect mice against clonic convulsions induced by intraperitoneally (i.p.) administered bupropion in the CD97 dose (139.5 mg/kg). Among 13 tested drugs, clonazepam showed the greatest potency (dose-dependent full protection; ED50 = 0.06 mg/kg, i.p.). No signs of locomotor impairment were observed in the rotarod test after anticonvulsive doses of clonazepam, resulting in a broad therapeutic window and favorable protective index (PI) (33.3). Gabapentin produced dose-dependent protection against convulsions at nontoxic doses (up to 1000 mg/kg), having PI>29. Diazepam in a very high dose showed full protection but its PI (1.7) was much less favorable than that of clonazepam. The PI values for ethosuximide, phenobarbital and valproate were slightly higher than unity and lower than 2, and for topiramate and felbamate were lower than unity. Phenytoin, carbamazepine, and lamotrigine as well as tiagabine failed to block the convulsant effects of bupropion even at doses that caused severe motor impairment. Our results encourage clinical testing of clonazepam against seizures developing after bupropion overdose.

Animals↗
PubMed2006

The role of voluntary exercise in enriched rearing: a behavioral analysis.

The effects of postweaning enriched rearing and home cage voluntary wheel-running exercise in adulthood were contrasted on a comprehensive battery of tests designed to assess mnemonic, attentional, emotional, and motor functions. In a 2 x 2 factorial design, female C57BL/6 mice were housed in groups in either standard or enriched cages, which were equipped with either a running or a locked wheel. They were maintained in the corresponding housing conditions for 2 months postweaning prior to, and throughout, testing. Enriched rearing was associated with anxiogenesis, hypolocomotor activity, enhanced motor skills, retarded extinction of conditioned responding, and improved water maze performance. Exercise as such enhanced motor coordination and facilitated extinction of contextual conditioning. Evidence for an interaction between enrichment and exercise was apparent in the open field test, conditioned freezing to a tone stimulus, prepulse inhibition, and acquisition of water maze reference memory. Hence, care should be taken to control for the unique contribution of wheel-running exercise when it is included as an integral component of the enrichment procedure.

Analysis of Variance↗
PubMed2005

Heterozygous mice with Ric-8 mutation exhibit impaired spatial memory and decreased anxiety.

Ric-8 is a guanine nucleotide exchange factor for a subset of Galpha proteins and it is required to maintain Galpha(q) and the Galpha(s) pathways in functional state. In adult mice Ric-8 is expressed in regions involved in the regulation of behavior (neocortex, cingulate cortex and hippocampus). As Ric-8 is shown to regulate neuronal transmitter release, the aim of present study was to perform behavioral analysis of ric-8 mutant. Homozygous (-/-) ric-8 mutant mice are not viable and die in early embryonic development, therefore for behavioral analysis heterozygous (+/-) ric-8 mutant mice were used. We found decreased anxiety of ric-8 heterozygous mice in light-dark compartment test where mutant mice significantly avoided the light compartment. In spatial learning paradigm (Morris water maze) the performance of ric-8 (+/-) mice was impaired. Namely, in the reversal test, ric-8 (+/-) mice exhibited significant delay to find the hidden platform compared to wild-type (wt) littermates. We did not find differences in the behavioral tests reflecting the motor abilities of mice (motor activity, rota-rod). Therefore, described alterations seem to be specific for anxiety and spatial learning. Based on these results we can conclude the importance of ric-8 in the regulation of memory and emotional behavior.

Animals↗