Exploratory Activity In Mice Research Articles

Spontaneous remyelination following dimethyl sulfoxide-induced demyelination is accompanied by behavioral and neurological alteration in mice

Introduction: Dimethyl sulfoxide (DMSO) is a commonly used solvent that can be applied in experimental studies for preparation of hydrophobic solutions as well as in capacity of a cryopreservative in transplantology. According to modern data acquired from in vitro experiments, DMSO is able to change the structure of myelin by decreasing synthesis of its main components and inhibiting oligodendrocyte genesis. Aim of the study: We studied influence of DMSO on anxiety and compulsive-like behavior, pain perception, motor coordination and myelin quantity in the corpus callosum of the C57BL/6 mice brain after prolonged oral administration of the solvent and 4 weeks after administration was stopped. Materials and Methods: All the experiments were conducted on male inbreed C57BL/6 mice. DMSO was added to drinking water to achieve 0.01% concentration, and the obtained solution was administered ad libitum for 6 weeks. After 6 weeks of administration of DMSO and 4 weeks after administration of DMSO was stopped, anxiety-like behavior in open field test, compulsive-like behavior in marble burying test, motor coordination in rotarod test, pain perception in tail-immersion test, as well as myelin quantity in the corpus callosum were evaluated. Results: It was established that DMSO consumed for 6 weeks was associated with decrease in the myelin quantity in thecorpus callosum and thermal hyperalgesia in tail-immersion test. During 4-week period after DMSO administration was stopped, attenuation of demyelination was observed, followed by an increase in thermal hyperalgesia in tail-immersion test, as well as vertical locomotion and exploratory activity in open field test. Conclusions: 6-week ad libitum administration of 0.01% DMSO solution was associated with demyelination in corpus callosum of С57BL/6 mice, followed by thermal hyperalgesia. Cessation of DMSO led to spontaneous remyelination with an increase in thermal hyperalgesia, vertical locomotion and exploratory activity of mice.

L-proline transporter inhibitor (LQFM215) promotes neuroprotection in ischemic stroke.

L-proline transporter (PROT/SLC6A7) is closely associated with glutamatergic neurotransmission, where L-proline modulates the NMDA receptor (NMDAR) function. NMDAR-mediated excitotoxicity is a primary cause of neuronal death following stroke, which is triggered by the uncontrolled release of glutamate during the ischemic process. After ischemic stroke, L-proline levels show a reduction in the plasma, but high circulating levels of this molecule indicate good functional recovery. This work aimed to produce new PROT inhibitors and explore their effects on ischemic stroke. Initially, we built a three-dimensional model of the PROT protein and run a molecular docking with the newly designed compounds (LQFM215, LQFM216, and LQFM217). Then, we synthesized new PROT inhibitors by molecular hybridization, and proline uptake was measured inex vivoandin vivomodels. The behavioral characterization of the treated mice was performed by the open-field test, elevated plus-maze, Y-maze, and forced swimming test. We used the permanent middle cerebral artery occlusion (MCAO) model to study the ischemic stroke damage and analyzed the motor impairment with limb clasping or cylinder tests. LQFM215 inhibited proline uptake in hippocampal synaptosomes, and the LQFM215 treatment reduced proline levels in the mouse hippocampus. LQFM215 reduced the locomotor and exploratory activity in mice and did not show any anxiety-related or working memory impairments. In the MCAO model, LQFM215 pre-treatment and treatment reduced the infarcted area and reduced motor impairments in the cylinder test and limb clasping. This dataset suggests that the new compounds inhibit cerebral L-proline uptake and that LQFM215 promotes neuroprotection and neuro-repair in the acute ischemic stroke model.

The Effect of Long-Term Moderate Static Magnetic Field Exposure on Adult Female Mice.

Because of the high cost and safety of ultra-high magnetic resonance imaging (MRI), its application has certain limitations. Whereas 0.5-3 T MRI has been widely applied in hospitals, static magnetic fields (SMFs) have been shown to improve mice mental health and have anti-tumor potentials. Here, we compared the effects of the upward and downward 150 mT SMF groups with the sham group on C57BL/6J adult female mice. Locomotor and exploratory activity were also measured by behavioral tests, including the open field and elevated plus test. Additionally, physiology, pathology indicators and gut microbiota were examined. We found that 150 mT SMFs long-term exposure enhanced locomotive and exploratory activity of mice, especially the downward 150 mT SMF. Compared with the downward 150 mT SMF group, the movement speed and distance in the center area of the sham group were increased by 65.99% (p < 0.0001) and 68.58% (p = 0.0038), respectively. Moreover, compared to the sham group, downward 150 mT SMF increased the number of entrances to the center area by 67.0% (p = 0.0082) and time in the center area by 77.12% (p = 0.0054). Additionally, we observed that upward 150 mT SMF improved the number of follicles (~2.5 times, p = 0.0325) and uterine glands through increasing the total antioxidant capacity and reducing lipid peroxidation level in mice. Gut microbiome analysis showed that 150 mT SMFs long-term exposure improved the microbiota abundance (Clostridium, Bifidobacterium, Ralstonia and Yaniella) in the genus level, which may affect metabolism, anxiety and behavior in adult female mice. Our results demonstrated that 150 mT SMFs long-term exposure not only had good biosafety, but also improved athletic performance, emotion and the function of ovarian, uterine and gut microbiota abundance in adult female mice, which unraveled the potential of moderate long-term SMF exposure in clinical applications.

Neuroprotective Effects of a Cholecystokinin Analogue in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Parkinson's Disease Mouse Model.

Parkinson’s disease (PD) is a chronic neurodegenerative disease. Type 2 diabetes mellitus (T2DM) has been identified as a risk factor for PD. Drugs originally developed for T2DM treatment such as liraglutide have shown neuroprotective effects in mouse models of PD. Cholecystokinin (CCK) is a peptide hormone with growth factor properties. Here, we demonstrate the neuroprotective effects of the (pGLu)-(Gln)-CCK8 analogue in an acute PD mouse model induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Administration of CCK analogue (50 nmol/kg ip.) for 14 days treatment improved the locomotor and exploratory activity of mice, and improved bradykinesia and movement balance of mice. The CCK analogue administration also restored tyrosine hydroxylase (TH) positive dopaminergic neurons number and synapse number (synaptophysin levels) in the substantia nigra pars compacta (SNpc). The CCK analogue decreased glia activation and neuroinflammation in the SNpc, and regulated autophagy dysfunction induced by MPTP. CCK analogue protected against mitochondrial damage and ER stress, and also decreased the ratio of apoptosis signaling molecules Bax/Bcl-2. Importantly, the CCK analogue improved the decrease of p-CREBS133 growth factor signaling in the SNpc. Therefore, the CCK analogue promotes cell survival of dopaminergic neuron in the SNpc by activating the cAMP/PKA/CREB pathway that also inhibits apoptosis and regulates autophagy impairment. The present results indicate that CCK analogue shows a promising potential for the treatment of PD.

Neuroprotective Effects of a GLP-2 Analogue in the MPTP Parkinson's Disease Mouse Model.

Glucagon-like peptide 2 (GLP-2) is a peptide hormone derived from the proglucagon gene expressed in the intestines, pancreas and brain. Some previous studies showed that GLP-2 improved aging and Alzheimer's disease related memory impairments. Parkinson's disease (PD) is a progressive neurodegenerative disorder, and to date, there is no particular medicine reversed PD symptoms effectively. The aim of this study was to evaluate neuroprotective effects of a GLP-2 analogue in the 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) PD mouse model. In the present study, the protease resistant Gly(2)-GLP-2 (50 nmol/kg ip.) analogue has been tested for 14 days by behavioral assessment, transmission electron microscope, immunofluorescence histochemistry, enzyme-linked immunosorbent assay and western blot in an acute PD mouse model induced by MPTP. For comparison, the incretin receptor dual agonist DA5-CH was tested in a separate group. The GLP-2 analogue treatment improved the locomotor and exploratory activity of mice, and improved bradykinesia and movement imbalance of mice. Gly(2)-GLP-2 treatment also protected dopaminergic neurons and restored tyrosine hydroxylase expression levels in the substantia nigra. Gly(2)-GLP-2 furthermore reduced the inflammation response as seen in lower microglia activation, and decreased NLRP3 and interleukin-1β pro-inflammatory cytokine expression levels. In addition, the GLP-2 analogue improved MPTP-induced mitochondrial dysfunction in the substantia nigra. The protective effects were comparable to those of the dual agonist DA5-CH. The present results demonstrate that Gly(2)-GLP-2 can attenuate NLRP3 inflammasome-mediated inflammation and mitochondrial damage in the substantia nigra induced by MPTP, and Gly(2)-GLP-2 shows neuroprotective effects in this PD animal model.

Influence of ketotifen and conventional antiepileptic drugs on the exploratory and spontaneous locomotor activity in mice

Abstract Drug interactions are major problems in polytherapy, especially in epilepsy, and inappropriate drug selection may result in increased frequency of seizures. In this study, the influence of histamine type 1 (H1) receptor antagonist ketotifen and four chosen antiepileptic drugs (AEDs) on mice activity was examined. We evaluated three parameters of locomotor activity in mice: horizontal total activity with total distance and vertical activity, as well as animal spontaneous activity. Experiments were divided into two 15-minutes studies. During the first 15 minutes, we examined exploratory activity in mice; in the second period, spontaneous activity was tested. In the experiment, Ketotifen or vehicle were administered once or for 7 days daily, whereas AEDs were given only once before test performance. Our results show that ketotifen given alone once or for 7 days significantly increased exploratory locomotor activity in mice without affecting their spontaneous activity. However, in combination with AEDs, ketotifen given once or for 7 days differently affected spontaneous and locomotor activity in mice. Our study indicates that the combination of ketotifen with AEDs needs special attention in pharmacotherapy of epilepsy.

Synthesis of 1,3,4-oxadiazoles derivatives with antidepressant activity and their binding to the 5-HT1A receptor.

In this study, two series of 1,3,4-oxadiazole derivatives were designed and synthesized using the forced swimming test (FST) model to test the antidepressant activity of the target compound in vivo. Five compounds with potential activity were selected from the FST model to test affinity with 5-HT1A receptor in vitro. The results of the FST experiment showed that compound N-(3-((5-((4-chlorobenzyl)thio)-1,3,4-oxadiazol-2-yl)methoxy)phenyl)acetamide (10g) showed the best antidepressant activity (DID = 58.93, percentage decrease in immobility duration in FST), similar to the activity of positive drug fluoxetine. Compound 10g also exhibited the most potent binding affinity to 5-HT1A receptors (Ki = 1.52 nM). The results of the in vivo 5-HT concentration estimation in mice showed that compound 10g may have an effect on the brain. The experimental results of exploratory activity in mice showed that compound 10g did not affect spontaneous activity in the open-field test model. Molecular docking was used to study the binding mode of compound 10g and the 5-HT1A receptor. Compound 10g showed significant interactions with residues at the active site on the 5-HT1A receptor. The physicochemical and pharmacokinetic properties of the target compounds were predicted using Discovery Studio 2019 and ChemBioDraw Ultra 14.

The effects of interleukin-10 and fibroblasts growth factor-2 in mice with toxic cuprizone model of demyelination

Cytokines and growth factors exhibit neurotropic, anti-inflammatory and immunomodulatory properties, and therefore can affect the functioning of the nervous system at demyelinating disorders.Purpose. To identify changes in T-lymphocytes, macrophages, oxidative stress and antioxidant defence factors, endocrine thymus function in the brain and behaviour of mice receiving neurotoxin cuprizone and recombinant human proteins: interleukin-10 (rhIL-10) and fibroblast growth factor (rhFGF-2).Materials and methods. 4-6-month-old 129/Sv mice received cuprizone with food every day for 3 weeks. From the 7th day of cuprizone diet, they received different doses of rhIL-10 and rhFGF-2. The content of СD3+ Т-cells, macrophages, malondialdehyde, activity of antioxidant enzymes in the brain and the level of thymulin in the blood were determined. Behavioural reactions were assessed in the “open field” test.Results. In the brain of mice receiving cuprizone and rhIL-10, there was a decrease in the number of СD3+ Т-cells and the activity of macrophages, which significantly increased under the influence of the toxin. After cytokine injection, the activity of superoxide dismutase, catalase and glutathione peroxidase increased significantly in the brain, as well as the level of thymulin in the blood. Motor, emotional and exploratory activity of mice, significantly suppressed by the cuprizone, was increased after the introduction of rhIL-10. The effect of rhIL-10 on the test parameters is more pronounced at a dose of 5 μg/kg than 50 μg/kg. After injection of rhFGF-2 in the mice with cuprizone diet, there is a decrease in the activity of brain macrophages and an increase of the level of thymulin in the blood depending on the dose of this factor; the motor activity of these animals increased regardless of the rhFGF-2 dose.Conclusion. The injections of rhIL-10 and rhFGF-2 provide dose-dependent positive effects on the pathogenetic factors of experimental demyelinating pathology, as well as the functional state of the nervous system. Whereas, the injections of rhIL-10 have more pronounced effects.

Neuropharmacological Screening of Sulfated Agaran Isolated from a Red Marine Alga Revel an Increase of the Exploratory Activity in Mice

Neuropharmacological Screening of Sulfated Agaran Isolated from a Red Marine Alga Revel an Increase of the Exploratory Activity in Mice

Neuroprotective effects of a GIP analogue in the MPTP Parkinson's disease mouse model

Parkinson's disease (PD) is a chronic neurodegenerative disease, and there is no cure for it at present. Recent research has indicated a link between type 2 diabetes mellitus (T2DM) and PD, which suggested that a treatment to improve insulin resistance for T2DM may be useful for PD patients. Glucose-dependent insulinotropic polypeptide (GIP) belongs to the incretin hormone family, which can promote insulin release and improve insulin resistance. Several GIP analogues have been developed as potential treatments for T2DM. In the present study, a novel long-lasting GIP analogue, D-Ala2-GIP-glu-PAL, has been tested in an acute PD mouse model induced by four 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intraperitoneal injections. D-Ala2-GIP-glu-PAL treatment (25 nmol/kg ip.) for 7 days after MPTP treatment improved the locomotor and exploratory activity of mice, and improved bradykinesia and movement balance of mice. D-Ala2-GIP-glu-PAL treatment also restored tyrosine hydroxylase (TH) positive dopaminergic neuron numbers in the substantia nigra and TH levels in the striatum. D-Ala2-GIP-glu-PAL also reduced the chronic inflammation response as seen in astrocyte and microglia activation in the substantia nigra pars compacta (SNpc). D-Ala2-GIP-glu-PAL reversed the reduction of synapse numbers (synaptophysin levels), decreased the ratio of growth factor and apoptosis signaling molecules Bax/Bcl-2, and improved the decrease of p-CREBS133 growth factor signaling in the substantia nigra. Therefore, D-Ala2-GIP-glu-PAL promotes cell survival of dopaminergic neuron in the SNpc by activating the cAMP/PKA/CREB growth factor second messenger pathway that also inhibits apoptosis. The present results demonstrate that D-Ala2-GIP-glu-PAL shows promise as a novel treatment of PD.

Benzodiazepines induce sequelae in immature mice with inflammation-induced status epilepticus.

Since benzodiazepines (BZPs) became clinically available for the treatment of status epilepticus (SE) in children, the incidence of neurological sequelae has increased. However, the cause-effect relationship is poorly understood. In this paper, we examined the effect of BZPs on an inflammation-induced SE (iSE) animal model. Inflammation was induced by injecting poly(I:C) (pIC 10 mg/kg, postnatal day 12-14), seizure was induced by injecting pilocarpine hydrochloride (PILO 200 mg/kg, postnatal day 15) into C57BL/6J mice, and the pIC+PILO mice were used as the iSE model (miSE). The GABA-A receptor agonist midazolam (MDL 0.5 mg/kg) was used to inhibit seizures. Sequelae were evaluated by performing behavior and immunohistochemical analyses in the chronic phase. The exploratory activity of mice in the miSE plus MDL group increased significantly, indicating that hyperactivity was newly induced by MDL in miSE mice. The contextual fear memory of the miSE mice was also significantly increased and that of miSE treated with MDL returned to the normal level. The parvalbumin-positive GABA neurons were decreased in number by pIC+PILO which was rescued by MDL. Apoptosis marker ssDNA-positive cells were increased by pIC+PILO which could not be rescued by MDL. Therefore, we propose that BZP-dependent therapy for SE needs to be rethought from the perspective of using other treatment approaches.

Neuroprotective effects of geniposide in the MPTP mouse model of Parkinson's disease

Parkinson's disease (PD) is a chronic neurodegenerative disease, and there is no cure for it at present. We tested the drug Geniposide, an active component of Gardenia jasminoides Ellis which is used in traditional Chinese medicine. Geniposide has shown neuroprotective and growth-factor like effects in several in vivo and in vitro studies. In the present study, Geniposide had been tested in an acute PD mouse model induced by four 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intraperitoneal injections. Geniposide treatment (100mg/kg ip.) for 8 days after MPTP treatment (30mg/kg ip.) improved the locomotor and exploratory activity of mice (open field), and improved bradykinesia and movement balance of mice (rotarod, swim test). Geniposide treatment also restored tyrosine hydroxylase (TH) positive dopaminergic neuron numbers in the substantia nigra pars compacta. Drug treatment also increased levels of growth factor signaling molecule Bax and reduced the apoptosis signaling molecule Bcl-2. Caspase 3 activation was also reduced in the substantia nigra. We conclude that Geniposide exerted its neuroprotective effect by enhancing growth factor signaling and the reduction of apoptosis. Geniposide is an ingredient in Chinese traditional medicine with few known side effects and shows potential as a drug treatment for Parkinson's disease.

Synthesis and psychobiological evaluation of modafinil analogs in mice

Background and the purpose of the studyModafinil, a novel wake-promoting agent with low potential for abuse and dependence, has a reliable structure to find some novel derivatives with better activity and lower potential for abuse and risk of dependency. This study was designed to evaluate psychobiological activity of some novel N-aryl modafinil derivatives.MethodsSeven novel N-aryl modafinil derivatives were synthesized through three reactions: a) preparation of benzhydrylsulfanyl acetic acid through reaction of benzhydrol with thioglycolic acid, b) formation of desired amide by adding the substituted aniline to activated acid with EDC (1-ethyl-3-(3-dimethyl amino propyl) carbodiimide). This reaction was catalyzed by HOBt (N- hydroxylbenzotriazole), and c) oxidation of sulfur to sulfoxide group with H2O2. Then, their psychobiological effect on the performance of male albino mice were compared to that of modafinil as following: wakefulness by determining the effects of derivatives on phenobarbital-induced loss of the righting reflex (LOPR); exploratory activity by measuring activity in the open field test (OFT); depression by measuring immobility time (IT) during forced swimming test (FST) and the anxiogenic and anxiolytic like effects by using elevated plus-maze test (EPM). All tests were videotaped and analyzed for the frequency and duration of the behaviors during the procedures.Conclusions2-(Benzhydrylsulfonyl)-N-(4-chlorophenyl)acetamide (4c) showed comparable result in LOPR test. However, all analogs were found to be stimulant except 2-(benzhydrylsulfinyl)-N-phenylacetamide (4a). Also 4c led the most exploratory activity in mice among derivatives. FST results showed that 4a had the longest IT while modafinil, 2-(benzhydrylsulfinyl)-N-(3-chlorophenyl) acetamide (4b) and 2-(benzhydrylsulfinyl)-N-(4-ethylphenyl) acetamide (4d) had the shortest IT. In EPM, all derivatives showed anxiogenic-like behavior since they decreased open arms time and open arms entries and simultaneously increased close arms time.

Neuropharmacological activities of <i>Ficus platyphylla</i> stem bark in mice

Methanol Extract Ficus platyphylla stem bark in dosages (17, 40 and 75, 150mg/kg) was found to produce a profound decrease in exploratory activity in mice, the extract indicated peripheral and central analgesic effects as shown by significant inhibition of acetic acid -induced writhing, and delayed onset in leptazol induced-convulsion (seizures) in micerespectively. It also decreases the rate of leptazol induced mortality in mice. The totality of these effects showed that the extract possesses depressant action on the central nervous system.

P.1.c.048 5-HT7 receptors interact with NMDA and 5-HT1A receptor-dependent emotional learning and exploratory activity in mice

P.1.c.048 5-HT7 receptors interact with NMDA and 5-HT1A receptor-dependent emotional learning and exploratory activity in mice

Exploratory activity of mice of different genetic strains after olfaction disruption by 3-methylindole (skatole)

The behavior of mice of two inbred strains (C57BL/6J and CBA) and their F1 hybrids was evaluated in the open field test after intraperitoneal administration of 3-methylindole (skatole) disrupting epithelium of the main olfactory system. High motor and exploratory activities and emotional sensitivity was observed in intact C57BL/6J mice compared to CBA mice and their hybrids. Anosmia induced by intraperitoneal administration of skatole changed the behavior of C57BL/6J and CBA mice. The direction of the observed changes in the orientation and exploratory behavior of anosmic animals was different. Anosmia decreased motor and exploratory activities in C57BL/6J mice and increase them in CBA mice. Intact hybrid mice demonstrated the predominance of the CBA genotype in the orientation and exploratory activity in the test used. Anosmia in hybrid animals had no significant effect on the orientation and exploratory behavior.

Effect of 5-HT 3 receptor antagonist MDL 72222 on behaviors induced by ketamine in rats and mice

Phencyclidine and ketamine (but not other NMDA channel blockers, such as memantine) produce psychotomimetic effects. Since unlike memantine, phencyclidine-like compounds show no significant affinity at 5-HT 3 receptors, we investigated if behavioral effects of ketamine could be reduced by 5HT 3 receptor blockade. Ketamine (3–40 mg/kg) produced ataxia, stereotypes and diminished exploratory activity in mice, and reduced prepulse inhibition of acoustic startle response, lowered accuracy in fixed consecutive number and in delayed non-matching-to-sample tasks in rats. The 5HT 3 receptor antagonist MDL 72222 (0.3–3 mg/kg) administration did not reverse any of these deficits and exerted no effects on discriminative stimulus properties of ketamine. In the tail suspension test, both ketamine and MDL 72222 produced anti-immobility effects when given alone (50–66 and 3 mg/kg, respectively) and together (12.5–25 and 1 mg/kg). The present data suggest that 5-HT 3 receptor blockade does not reverse the behavioral deficits of ketamine and may even enhance its certain effects, such as the antidepressant-like action.

Liver-derived IGF-I regulates exploratory activity in old mice

Growth hormone (GH) replacement in hypopituitary patients improves well-being and initiative. Experimental studies indicate that these psychic effects may be reflected in enhanced locomotor activity in mice. It is unknown whether these phenomena are mediated directly by GH or by circulating IGF-I. IGF-I production in the liver was inactivated at 6-10 wk of age (LI-IGF-I-/- mice), resulting in an 80-85% reduction of circulating IGF-I, and, secondary to this, increased GH secretion. Using activity boxes on three different occasions during 1 wk, 6-mo-old LI-IGF-I-/- mice had similar activity levels, and 14-mo-old mice had a moderate but significant decrease in activity level, compared with control mice. At 20 mo of age, the LI-IGF-I-/- mice displayed a more prominent decrease in activity level with decreased horizontal activity throughout the test period, and at day 1, there were several signs of an altered habituation process with different time patterns of locomotor activity and horizontal activity compared with the control mice. At days 3 and 5, rearing activity was lower in the 20-mo-old LI-IGF-I-/- mice. Anxiety level was unaffected in all age groups, as measured using the Montgomery's elevated plus-maze. In conclusion, old LI-IGF-I-/- mice displayed a decrease in both horizontal and rearing (exploratory) activity level and an altered habituation process. These results indicate that liver-derived IGF-I mediates at least part of the effects of GH on exploratory activity in mice.

Behavioural effects in rodents of methyl angolensate: a triterpenoid isolated from Entandrophragma angolense.

Behavioral effects of methyl angolensate were investigated in mice and rats. Spontaneous motor activity, pentobarbital sleeping time, amphetamine-stereotyped behaviour, exploratory activity and apomorphine-induced climbing studies in mice were evaluated. The results revealed that methyl angolensate reduced spontaneous motor activity in mice, prolonged the duration of pentobarbital sleeping time in rats and attenuated amphetamine-induced stereotype behaviour in rats. Methyl angolensate also decreased exploratory activity in mice and reduced the rate of apomorphine-induced climbing in mice at the doses tested. It is suggested that methyl angolensate possesses some biologically active principles that are sedative in nature.

The effects of flumazenil, Ro 154513 and beta-CCM on the behaviour of control and stressed mice in the staircase test.

The effects of flumazenil, Ro 154513 and beta-CCM in the staircase test were studied in control and small platform (SP) stressed mice. SP stress was induced by placing mice on small platforms (3.5 cm in diameter) surrounded by water for 24 h. This model contains several factors of stress, such as rapid eye movement sleep deprivation, isolation, immobilization and falling into the water. The staircase test consisted of placing a mouse in an enclosed staircase with five steps and recording: (i) the number of rearings and (ii) steps made during 3 min. SP stress increased the exploratory activity of mice in the staircase test as demonstrated by an increase in the number of rearings and steps made. In control mice flumazenil (2.0 and 10.0 mg/kg), Ro 15-4513 (1.0 and 3.0 mg/kg) and beta-CCM (1.0 and 2.0 mg/kg) exerted an anxiogenic effect that was demonstrated by an increase in the number of rearings without significant changes in the number of steps. Similar to control mice, flumazenil induced an anxiogenic effect in SP stressed mice as demonstrated by an increase in the number of rearings. However, the sedative effect of flumazenil as demonstrated by a decrease in the number of steps made was more pronounced in SP stressed mice. In the SP stressed mice, the anxiogenic effect of Ro 15-4513 and beta-CCM was masked by their strong sedative effect and a decrease in both measures of exploratory activity (number of rearings and number of steps). These data suggest that SP stress induces hypersensitivity to the sedative effect of flumazenil, Ro 15-4513 and beta-CCM in the staircase test.