D-Cycloserine enhances social exploration in the Balb/c mouse

Inbred Balb/c mice show deficits of sociability. The endogenous tone of NMDA receptor-mediated neurotransmission is altered in Balb/c mice, which may explain the beneficial effect of D-cycloserine on impaired sociability. In the current study, Balb/c mice spent more time than the Swiss Webster comparator strain in the open arms of an elevated plus maze (EPM), suggesting that they are not more anxious or fearful in the absence of a social stimulus mouse. Moreover, Balb/c and Swiss Webster mice did not differ in the amount of time they spent exploring an inanimate object in an open field. Differences in exploratory activity between strains emerged only when a salient social stimulus mouse was enclosed in the open field. D-Cycloserine increased the amount of time Balb/c mice spent exploring the enclosed stimulus mouse to levels observed in vehicle-treated Swiss Webster mice. Finally, irrespective of strain, D-cycloserine increased exploratory activity as measured in open arm entries in the EPM, when no enclosed stimulus mouse was present. The data show that mouse strain influences D-cycloserine's effect on exploration in the presence of a salient social stimulus mouse. In the absence of an enclosed stimulus mouse, D-cycloserine increased open arm entries significantly in both the sociability-impaired Balb/c and comparator Swiss Webster strains. Thus, D-cycloserine positively affects exploratory activity in general, but strain differences emerge when the stimulus eliciting exploration is a salient social stimulus mouse versus an inanimate object. Further, the sociability deficit of the Balb/c mouse is not an epiphenomenon of increased generalized anxiety.     

d-Cycloserine improves sociability in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorders with altered Ras/Raf/ERK1/2 signaling

The genetically inbred BTBR T+ Itpr3tf/J (BTBR) mouse is a proposed model of autism spectrum disorders (ASDs). Similar to several syndromic forms of ASDs, mTOR activity may be enhanced in this mouse strain as a result of increased Ras signaling. Recently, d-cycloserine, a partial glycine_B site agonist that targets the NMDA receptor, was shown to improve the sociability of the Balb/c mouse strain, another proposed genetically inbred model of ASDs. NMDA receptor activation is an important regulator of mTOR signaling activity. Given the ability of d-cycloserine to improve the sociability of the Balb/c mouse strain and the regulatory role of the NMDA receptor in mTOR signaling, we wondered if d-cycloserine would improve the impaired sociability of the BTBR mouse strain. d-Cycloserine (320 mg/kg, ip) improved measures of sociability in a standard sociability paradigm and spontaneous grooming that emerged during social interaction with an ICR stimulus mouse in the BTBR strain; however, similar effects were observed in the Swiss Webster comparator strain, raising questions about their strain-selectivity. Importantly, the profile of d-cycloserine’s effects on both measures of sociability and stereotypies is consistent with that of a desired medication for ASDs; specifically, a desired medication would not improve sociability at the expense of worsening stereotypic behaviors or vice versa.     

Complex effects of mGluR5 antagonism on sociability and stereotypic behaviors in mice: possible implications for the pharmacotherapy of autism spectrum disorders

Balb/c mice display deficits of sociability; for example, they show reduced locomotor activity in the presence of an enclosed or freely-moving social stimulus mouse. Transgenic mice with defective or diminished expression of NMDA receptors manifest impaired sociability, while a partial and full agonist of the obligatory glycine co-agonist binding site on the NMDA receptor improved sociability in the Balb/c mouse strain. Because 2-methyl-6-(phenylethynyl)-pyridine (MPEP), an antagonist of the mGluR5 metabotropic glutamate receptor (mGluR), reduced self-grooming behavior in BTBR T+tfJ (BTBR) mice, another inbred genetic mouse model of autism spectrum disorders (ASDs), and mGluR5 antagonism is emerging as an experimental treatment for the 'fragile X syndrome," which has a high prevalence of co-morbid ASDs, we examined the effects of MPEP on sociability and stereotypic behaviors in Balb/c and Swiss Webster mice in a standard paradigm. MPEP had complex effects on sociability, impairing some measures of sociability in both strains, while it reduced the intensity of some spontaneous measures of stereotypic behaviors emerging during free social interaction in Swiss Webster mice. Conceivably, mGluR5 antagonism exacerbates diminished endogenous tone of NMDA receptor-mediated neurotransmission in neural circuits relevant to at least some measures of sociability in Balb/c mice; the mGluR5 receptor contributes to regulation of the phosphorylation status of the NMDA receptor. In any event, although stereotypies are an important therapeutic target in ASDs, medication strategies to attenuate their severity via antagonism of mGluR5 receptors must be pursued cautiously because of their potential to worsen at least some measures of sociability.     

Strain differences in the extent of brain injury in mice after tetramethylenedisulfotetramine-induced status epilepticus

Acute intoxication with tetramethylenedisulfotetramine (TETS) can trigger status epilepticus (SE) in humans. Survivors often exhibit long-term neurological effects, including electrographic abnormalities and cognitive deficits, but the pathogenic mechanisms linking the acute toxic effects of TETS to chronic outcomes are not known. Here, we use advanced in vivo imaging techniques to longitudinally monitor the neuropathological consequences of TETS-induced SE in two different mouse strains. Adult male NIH Swiss and C57BL/6J mice were injected with riluzole (10 mg/kg, i.p.), followed 10 min later by an acute dose of TETS (0.2 mg/kg in NIH Swiss; 0.3 mg/kg, i.p. in C57BL/6J) or an equal volume of vehicle (10% DMSO in 0.9% sterile saline). Different TETS doses were administered to trigger comparable seizure behavior between strains. Seizure behavior began within minutes of TETS exposure and rapidly progressed to SE that was terminated after 40 min by administration of midazolam (1.8 mg/kg, i.m.). The brains of vehicle and TETS-exposed mice were imaged using in vivo magnetic resonance (MR) and translocator protein (TSPO) positron emission tomography (PET) at 1, 3, 7, and 14 days post-exposure to monitor brain injury and neuroinflammation, respectively. When the brain scans of TETS mice were compared to those of vehicle controls, subtle and transient neuropathology was observed in both mouse strains, but more extensive and persistent TETS-induced neuropathology was observed in C57BL/6J mice. In addition, one NIH Swiss TETS mouse that did not respond to the midazolam therapy, but remained in SE for more than 2 h, displayed robust neuropathology as determined by in vivo imaging and confirmed by FluoroJade C staining and IBA-1 immunohistochemistry as readouts of neurodegeneration and neuroinflammation, respectively. These findings demonstrate that the extent of injury observed in the mouse brain after TETS-induced SE varied according to strain, dose of TETS and/or the duration of SE. These observations suggest that TETS-intoxicated humans who do not respond to antiseizure medication are at increased risk for brain injury.     

Behavioural analysis of four mouse strains in an anxiety test battery

Differences in locomotor activity, exploratory activity and anxiety-like behaviour of C57BL/6ChR,C57BL/6J, Swiss Webster/J and A/J strain were investigated in an anxiety battery. The battery consisted of paradigms studying spontaneous behaviour after a mild stressor, tasks of innate anxiety (light-dark box, elevated plus maze, novel object exploration), response to a conflict situation (Vogel conflict), conditioned fear and response to inescapable swim stress. Locomotor activity was studied in an open field and compared with locomotion in the other tests. Exploratory behaviour was studied in a 16-hole board task. The data confirm previous studies suggesting that A/J mice are a relatively anxious strain. Also, the data indicated that locomotor activity was independent of the paradigm employed, while the rank order of strain-dependent effects on anxiety-related behaviour changed as a function of the task under study. Our data provide further support for the notion that choice of strain is essential in studies of anxiety-related behaviour. Influence of strain should be considered in pharmacological and lesion studies, as well as in studies with mutant mice. In addition, the data indicate that different anxiety paradigms tax different aspects of anxiety, suggesting that a battery of different tests should be used in studies of anxiety-related behaviour.     

Different ω-conotoxins mark the development of Swiss Webster mouse cortex suggesting N-Type voltage sensitive calcium channel subtypes

ω-GVIA conotoxin has been used to mark presynaptic N-type voltage sensitive calcium channels (VSCC).³,¹³,¹⁹,^21–23 Litzinger et al.⁹ used ω-conotoxin binding to describe a critical period of neurodevelopment in Swiss Webster mice between postnatal days (PND) 11 and 14, which appears to be important to the initiation of proper final development of the central nervous system. In this study, we compare how three different ω-conotoxins (i.e. GVIA from Conus geographus, MVIIA from Conus magus, and RVIA from Conus radiatus) mark N-type VSCC during this critical period in Swiss Webster mouse cortex. ¹²⁵I-GVIA was bound to Swiss Webster mouse cortex synaptosomal membrane fractions at postnatal days 8 and 14. ¹²⁵I-GVIA binding displacement curves were obtained by incubating membranes with increasing concentrations of unlabeled GVIA, MVIIA, and RVIA. Displacement curves and IC₅₀ were calculated for each of these three ω-conotoxins, and then compared. At PND 14, GVIA, MVIIA and RVIA were able to displace greater than 95% of ¹²⁵I-GVIA binding. At PND 8, however, MVIIA was only able to displace 83% of ¹²⁵I-GVIA binding, and RVIA was only able to block 84%. The IC₁₅₀ does not appear to change significantly during this period of development for any of the ω-conotoxins. The inability of MVIIA and RVIA to completely block ¹²⁵I-GVIA binding in pre-critical period Swiss Webster cortex denotes an alteration in the composition of N-type VSCC binding sites. With this data, we have suggested the presence of subtypes of the N-type VSCC in the cortex of pre-critical period Swiss Webster mouse.     

Glia cell number modulates sensitivity to MPTP in mice

Free radical damage has been shown to play a significant role in the pathogenesis of a number of neurodegenerative diseases including Parkinson's disease. One model of experimental parkinsonism is the loss of substantia nigra cells following administration of MPTP. Previously, it has been shown that a number of inbred strains of mice have differential responses to this toxin, and this difference is dependent on glial cells. In this study, the number of glial cells in the substantia nigra pars compacta of C57Bl/6J (MPTP-sensitive) and Swiss Webster (MPTP-resistant) strains of mice was examined. The C57Bl/6J mice have an approximately 50% lower number of GFAP+ and S-100beta glial cells than the Swiss Webster mice. C57Bl/6J mice have a 25% increased number of resident nonactivated microglial cells. To determine whether this difference in cell number has functional significance, we used an in vitro SN culture system that allowed us to manipulate the number of glial cells. When C57Bl/6 neurons were grown on a glial mat plated with twice the number of cells, we were able to rescue the MPTP-sensitive neurons from toxin-induced cell death. This suggests that the number of glial cells in the SNpc may be an important factor in the survival of dopaminergic neurons following exposure to xenobiotics.     

The effect of varying doses of d-amphetamine on activity levels of prepubertal mice

The effect of varying doses of d-amphetamine on the activity level of C57BL/6J mice (known for their high activity level), DBA/1J, C3H/HeJ, and C₃D₂F₁ mice was investigated (all mice were 25 to 30 days old). Activity was measured by the use of an activity cage with a revolving drum. After determination of baseline activity level, the animals were assigned to the following set of i.p. injections: (1) normal saline, (2) d-amphetamine 0.2mg/kg, (3) d-amphetamine 0.5 mg/kg, (4) d-amphetamine 5mg/kg. The mean activity level of the C57BL/6J mice was significantly higher than that of the other strains. The mean activity level after 5 mg/kg was significantly lower than after other dosages in all strains. All strains responded similarly to d-amphetamine as is apparent from the parallel profiles for the dose-response curves. The response of the developing mice to d-amphetamine is at variance with the known response of mature mice.     

In vivo regulation of mu-opioid receptor density and gene expression in CXBK and outbred Swiss Webster mice

Chronic in vivo treatment with the opioid agonist etorphine downregulates mu-opioid receptor density, produces tolerance, and regulates gene expression in the mouse. After cessation of treatment, there is an increase in mu-opioid receptor mRNA level associated with the recovery of mu-opioid receptors. However, the effect of etorphine on the regulation of mRNA during treatment is currently not known. In this study, etorphine-induced changes in mu-opioid receptor density, mRNA, and opioid analgesic potency were determined in two mouse strains that differ in basal mu-opioid receptor density in brain. CXBK mice (mu-opioid receptor deficient) and outbred Swiss Webster mice were implanted s.c. with placebo pellets (controls) or etorphine minipumps (250 microg/kg/day) for 1-7 days and mu-opioid receptor density or mRNA levels in whole brain were assessed or mice were tested for etorphine analgesia following 7 days of treatment. In control CXBK mice, mu-receptor density was approximately 40% less than that for the Swiss Webster, although mRNA abundance was similar in both strains. Etorphine's potency was 4-fold greater in control Swiss Webster compared to CXBK mice. Etorphine treatment decreased ( approximately 25-40%) mu-receptor density similarly in both strains throughout treatment. The magnitude of analgesic tolerance to etorphine was 8-fold in both mouse strains. Etorphine produced a biphasic effect on receptor mRNA in both strains with levels decreased (25%) by 3 days and increased (30-40%) at 7 days. mRNA levels remained elevated (55%) 16 h following the end of the 7 day etorphine treatment. Taken together, these data suggest that in vivo etorphine treatment that produces mu-opioid receptor downregulation and tolerance, can regulate mu-opioid receptor mRNA abundance. Receptor downregulation may initially induce decreases in mRNA levels since downregulation preceded a decrease in gene expression. Prolonged (>3 days) receptor downregulation may be responsible for increasing message levels and may be important in recovery of receptors following treatment. In addition, the magnitude of changes in receptor density, mRNA, and tolerance were similar in both CXBK and Swiss Webster mice, indicating that the mechanisms required for receptor regulation and its functional consequences are independent of basal mu-opioid receptor density.     

Study of the modulatory activity of BZ (omega) receptor ligands on defensive behaviors in mice: evaluation of the importance of intrinsic efficacy and receptor subtype selectivity.

1. This study examined the hypothesis that the anxiolytic effects of benzodiazepine (BZ (omega)) receptor ligands may be associated with actions at a defined receptor subtype and/or their level of intrinsic activity using the mouse defense test battery. 2. This test has been designed to assess defensive reactions of Swiss mice confronted with a natural threat (a rat) and situations associated with this threat. Primary measures taken before, during and after rat confrontation were escape attempts, flight, risk assessment and defensive threat and attack. 3. The drugs used were the non-selective BZ (omega) receptor full agonist diazepam, the non-selective BZ (omega) receptor partial agonist bretazenil and the beta-carboline abecarnil which acts as a full agonist on GABAA receptors containing the alpha 1- and the alpha 3-subunits and as a partial agonist at receptors containing the alpha 2- and the alpha 5-subunits. The drugs were given alone and diazepam was co-administered with either bretazenil or abecarnil. 4. When administered alone, diazepam attenuated several defensive responses including risk assessment activities, defensive threat/attack reactions upon forced contact with the rat and escape attempts following the removal of the rat from the apparatus. Unlike diazepam, bretazenil was devoid of significant activity on defense and abecarnil displayed depressant activity. 5. Bretazenil blocked all behavioral effects of diazepam on defense behaviors. The co-administration of diazepam and abecarnil produced a behavioral profile similar to that observed when diazepam was administered alone, indicating that abecarnil did not influence the effects of diazepam on defense. By contrast, diazepam completely antagonized the sedative effects of abecarnil. 6. These findings indicate that only BZ (omega) ligands with high intrinsic efficacy at all BZ (omega) receptor subtypes display clear and specific effects on defensive behaviors in mice, and suggest that GABAA receptors containing the alpha 3 subunit might represent the primary target involved in the modulatory action of diazepam on defensive behaviors.     

Naloxone-precipitated morphine withdrawal behavior and brain IL-1β expression: comparison of different mouse strains

The development of opioid dependence involves classical neuronal opioid receptor activation and is due in part to engagement of glia causing a proinflammatory response. Such opioid-induced glial activation occurs, at least in part, through a non-classical opioid mechanism involving Toll-like-receptor 4 (TLR4). Among the immune factors released following the opioid-glia-TLR4 interaction, interleukin-1β (IL-1β) plays a prominent role. Previous animal behavioral studies have demonstrated significant heterogeneity of chronic morphine-induced tolerance and dependence between different mouse strains. The aim of this study was to investigate whether the heterogeneity of chronic opioid-induced IL-1β expression contributes to differences in opioid tolerance and withdrawal behaviors. Chronic morphine-induced tolerance and dependence were assessed in 3 inbred wild-type mouse strains (Balb/c, CBA, and C57BL/6) and 2 knockout strains (TLR4 and MyD88). Analysis of brain nuclei (medial prefrontal cortex, cortex, brain stem, hippocampus, and midbrain and diencephalon regions combined) revealed that, of inbred wild-type mice, there are significant main effects of morphine treatment on IL-1β expression in the brain regions analyzed (p < 0.02 for all regions analyzed). A significant increase in hippocampal IL-1β expression was found in C57BL/6 mice after morphine treatment, whilst, a significant decrease was found in the mPFC region of wild-type Balb/c mice. Furthermore, the results of wild-type inbred strains demonstrated that the elevated hippocampal IL-1β expression is associated with withdrawal jumping behavior. Interestingly, knockout of TLR4, but not MyD88 protected against the development of analgesic tolerance. Gene sequence differences of IL - 1β and TLR4 genes alone did not explain the heterogeneity of dependence behavior between mouse strains. Together, these data further support the involvement of opioid-induced CNS immune signaling in dependence development. Moreover, this study demonstrated the advantages of utilizing multiple mouse strains and indicates that appropriate choice of mouse strains could enhance future research outcomes.     

Influence of spontaneous activity on peak-ratio analysis

Objectives: To prove or disprove the assumption that in neuropathy patients with abundant spontaneous activity, peak-ratio interference pattern analysis may lead to false negative results.Methods: Spontaneous activity >100 μV, automatically analysed by turn/amplitude analysis and expressed as (turns/second)/2 ((T/S)/2), and interference patterns, analysed by the peak-ratio technique, were recorded, one after the other, from the right anterior tibial muscle of 21 patients with neuropathy, aged 36–87 years.Results: The mean number of spontaneous discharges ((T/S)/2) was 12.3 (range 5.5–26) and its mean amplitude 261 μV (range 146–478 μV). Despite this abundant spontaneous activity, peak-ratio analysis was neurogenic in 81% of the patients. All peak-ratio parameters were independent on the amount and amplitude of spontaneous discharges.Conclusions: Spontaneous discharges >100 μV could be adequately assessed by means of the turn/amplitude analysis and did not influence peak-ratio analysis in neuropathies.     

Motor activity and the mesotelencephalic dopamine function. II. Multivariate analysis of genetically segregating generations.

Previous experiments on genetically different inbred strains of mice demonstrated parallel variations between the activity of regional brain tyrosine hydroxylase (TH) and locomotor behavior. Based on these associations, it was hypothesized that genetic variations in mesotelencephalic TH activity, an index of dopamine neurotransmitter function, would correlate positively with exploratory and locomotor behavior. In order to test this hypothesis, open-field motor behaviors and mesencephalic and striatal TH activities were analyzed by multivariate statistical methods in genetically segregating (C57BL/6ByJ X BALB/cJ)F2 and (C57BL/6ByJ X CXBI/ByJ)F2 generations. Factor analysis, based on correlation matrices of variables with significant genetic dominance or additive effects, demonstrated that locomotor activity and frequency of occurrence of various motor patterns were not correlated with mesencephalic and striatal TH activity. These results indicate that the assumption of a positive phenotypic correlation between spontaneous motor activity and mesotelencephalic TH activity does not hold in genetically segregating populations. Strategies and problems in revealing the behavioral consequences of genetically based variations in the mesotelencephalic DA system are briefly discussed.     

Long-term exposure to intranasal oxytocin in a mouse autism model

Oxytocin (OT) is a neuropeptide involved in mammalian social behavior. It is currently in clinical trials for the treatment of autism spectrum disorder (ASD). Previous studies in healthy rodents (prairie voles and C57BL/6J mice) have shown that there may be detrimental effects of long-term intranasal administration, raising the questions about safety and efficacy. To investigate the effects of OT on the aspects of ASD phenotype, we conducted the first study of chronic intranasal OT in a well-validated mouse model of autism, the BTBR T+ Itpr3tf/J inbred strain (BTBR), which displays low sociability and high repetitive behaviors. BTBR and C57BL/6J (B6) mice (N=94) were administered 0.8  IU/kg of OT intranasally, daily for 30 days, starting on day 21. We ran a well-characterized set of behavioral tasks relevant to diagnostic and associated symptoms of autism, including juvenile reciprocal social interactions, three-chambered social approach, open-field exploratory activity, repetitive self-grooming and fear-conditioned learning and memory, some during and some post treatment. Intranasal OT did not improve autism-relevant behaviors in BTBR, except for female sniffing in the three-chambered social interaction test. Male saline-treated BTBR mice showed increased interest in a novel mouse, both in chamber time and sniffing time, whereas OT-treated male BTBR mice showed a preference for the novel mouse in sniffing time only. No deleterious effects of OT were detected in either B6 or BTBR mice, except possibly for the lack of a preference for the novel mouse''s chamber in OT-treated male BTBR mice. These results highlight the complexity inherent in understanding the effects of OT on behavior. Future investigations of chronic intranasal OT should include a wider dose range and early developmental time points in both healthy rodents and ASD models to affirm the efficacy and safety of OT.     

Sex differences in thermal nociception and morphine antinociception in rodents depend on genotype

It has been appreciated for some time that the sexes can differ in their sensitivity to pain and its inhibition. Both the human and rodent literatures remain quite contentious, with many investigators failing to observe sex differences that others document clearly. Recent data from our laboratory have pointed to an interaction between sex and genotype in rodents, such that sex differences are observed in some strains but not others. However, these studies employed inbred mouse strains and are thus not directly relevant to existing data. We presently examined whether the observation of statistically significant sex differences in nociception and morphine antinociception might depend on the particular outbred rodent population chosen for study. Rats of both sexes and three common outbred strains were obtained from three suppliers (Long Evans, Simonsen; Sprague Dawley, Harlan; Wistar Kyoto, Taconic) and tested for nociceptive sensitivity on the 49 degrees C tail-withdrawal assay, and antinociception following morphine (1-10mg/kg, i.p.). In further studies, three outbred populations of mice (CD-1, Harlan; Swiss Webster, Harlan; Swiss Webster, Simonsen) were bred in our vivarium for several generations and tested for tail-withdrawal sensitivity and morphine antinociception (1-20male, and no significant difference. In a separate study in which the estrous cycle was tracked in female mice, we found evidence for an interaction between genotype and estrous phase relevant to morphine antinociception. However, estrous cyclicity did not explain the observed sex differences. These data are discussed with respect to the existing sex difference and pain literature, and also as they pertain to future investigations of these phenomena.     

Voltage-Sensitive Calcium Channel Development in Epileptic DBA/2J Mice Suggests Altered Presynaptic Function

Summary: Aberrant synapse formation has been implicated in development and propagation of epileptic potential. Litzinger et al. (1993a) showed that ω-GVIA conotoxin may be used as a marker for synapse formation in nonepileptic mice. We conducted ω-GVIA binding in synaptosomal preparations from epileptic DBA/2J mice at different developmental ages. Binding in DBA/2J mice was compared with ω-GVIA binding in synaptosomal preparations from nonepileptic C57/B1, Swiss Webster, and AJ mice. Striking differences between these strains of mice are evident in the developmental sequence and pattern of N-type voltage-sensitive calcium channels (VSCC). In contrast to nonepileptic mice, the DBA/2J mice show a slow increase in ω-GVIA binding between postnatal days 2 and 8. This increase corresponds to onset of susceptibility to seizure in this strain. In addition to the difference in developmental sequence, DBA/2J mice have fewer binding sites for ω-GVIA throughout development, suggesting changes in channel structure or number. These data show that in DBAI2J mice development of the VSCC in brain is different from that in nonepileptic mice. This difference in development in presynaptic membranes responsible for neurotransmitter release may represent a change in synaptic activity that plays a role in epileptogenesis.     

Evidences for B6C3-Tg (APPswe/PSEN1dE9) Double-Transgenic Mice Between 3 and 10 Months as an Age-Related Alzheimer’s Disease Model

Transgenic mouse has shown great advantages in the study of Alzheimer’s disease (AD) and drug screening as AD develops rapidly resent years, while more detail information of these transgenic mice and experience of application are needed. To obtain the basic background information of the B6C3-Tg (APPswe/PSEN1dE9) double-transgenic mouse, which was reported with early onset AD, three- to ten-month-old B6C3-Tg AD mice and normal C57BL/6 mice were selected randomly to test the ability of learning memory by Morris water maze, the brain acetylcholinesterase (AChE) activity by AChE kit, and beta amyloid protein level by immunohistochemistry staining. Compared with the control group, the escape latency time of B6C3-Tg AD mice at 9 and 10 months of age is significantly longer (P?<?0.05) in Morris maze test, and the activity of brain AChE is higher. β-Amyloid plaques were observed at 3 months of age and developed rapidly. Statistical analysis showed a positive correlation between the area of these plaques and the ages of B6C3-Tg AD mouse (y?=?0.0355e^0.5557x, R?=?0.9557). The model’s behavior is conformed to simulate behaviors of human Alzheimer’s disease at the early stage and may provide detail background information a new choice when transgenic mice are needed in the research of AD.     

Attenuation of nociceptive responses by ACEA-1021, a competitive NMDA receptor/glycine site antagonist, in the mice

Intrathecal administration of N-methyl- -aspartate (NMDA) and non-NMDA receptor antagonists has been shown to produce antinociception in various animal models of pain. In the present study we examined the effect of 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (ACEA-1021), a competitive NMDA receptor/glycine site antagonist, on nociceptive responses in the tail flick and formalin tests in mice. Swiss Webster mice were injected with ACEA-1021 intraperitoneally (1–60 mg/kg), or intrathecally (1–40 μg/mouse), and tested for antinociception. Systemic administration of ACEA-1021 attenuated the nociceptive responses solely in the formalin test. Nevertheless, intrathecal administration of ACEA-1021 showed equally potent attenuation of nociceptive responses in both animal models of pain. The effect of ACEA-1021 was also examined on caudally directed biting and scratching (CDBS) behaviors induced by intrathecal administration of NMDA. Microinjections of NMDA (1–1000 μM) in the spinal cord produced dose-dependent CDBS behaviors. Mice pretreated with ACEA-1021 (0.5–40 μg/mouse) showed dose-dependent protection against CDBS behaviors induced by intrathecal NMDA. Taken together, the results suggest that ACEA-1021 may block spinal NMDA receptors to attenuate nociceptive responses, however, our data cannot exclude the involvement of non-NMDA receptors.     

Home cage activity and behavioral performance in inbred and hybrid mice

Locomotor activity is a key component in many behavioral tests, suggesting that genetic differences in activity levels may be a critical consideration when comparing mouse strains. In order to assess the relationship between activity and performance, we recorded home cage activity, and locomotion and defecation, a non-activity-linked behavior, in tests of anxiety in inbred (C57BL/6J (B6), n = 25; BALB/cJ (C), n = 24; DBA/2J (D2), n = 28) and hybrid (CB6F1/6J (CB6: B6 x C) n = 19) mice. Under our test conditions, the strains showed significant differences in home cage activity levels: C > B6 > D2. The CB6 mice were similar to the B6 mice in horizontal activity and were intermediate between the parental strains in vertical movement. Based on measures of locomotion and defecation in the open field, emergence and novel object tests, and the elevated zero maze, the C mice appeared to be the most anxious and the B6 were the least anxious. The D2 mice were intermediate on some measures but more similar to B6 mice on others, making ranking them more difficult. In addition, the CB6 mice displayed characteristics of both parental strains. They had greater similarity to B6 mice in measures of horizontal movement in the home cage and locomotion in the open field and emergence tests, but exhibited defecation responses similar to those of C mice in the novel object test and elevated zero maze. The results suggest that strain differences in spontaneous locomotion should be considered when interpreting strain differences in behavioral tests, and that home cage activity may be a useful interpretive aid.