Effect of plant melanin pigment on the clastogenic effects of chemical mutagens in mice

The chromosome aberration assay in the bone marrow cells of C57BL/6 mice showed that melanin pigment (MP) in a dose range from 0.01 to 10 mg/kg does not influence the clastogenic effect of dioxidine (200 mg/kg, i.p.), while reducing the clastogenic effect of cyclophosphamide (20 mg/kg, i.p.) by a factor of 1.5-4 in various treatment regimes depending on the mutagen injection time.     

The influence of verapamil on the clastogenic effect of cyclophosphane in somatic cells from BALB/c and C57Bl/6 mice]

The method of chromosome aberration count in the bone marrow cells of male BALB/c and C57Bl/6 mice was used to study the influence of intraperitoneal injection of verapamil in doses of 0.1-10 mg/kg and its administration into the stomach in doses of 2.5-10 mg/kg on the clastogenic effect of cyclophosphamide (10 mg/kg intraperitoneally) in a single and repeated (5 times at intervals of 24 h) administration. In repeated administration in all the doses used, verapamil significantly intensified the mutagenic activity of cyclophosphamide in C57Bl/6 mice and in doses 10 mg/kg in BALB/c mice. A single intraperitoneal verapamil injection (0.1-0.4 mg/kg) caused a statistically increase in the clastogenic effect of cyclophosphan in mice of both strains. The same effect was encountered in intraperitoneal injection (2.5 mg/kg) and administration into the stomach (5 mg/kg) of the calcium antagonist in BALB/c mice. Thus, the effect of verapamil on cyclophosphamide clastogenic activity depends on the dose, method, and schedule of administration of the calcium antagonist.     

The antimutagenic activity of afobazol studied in vivo

The chromosome aberration assay in the bone marrow cells of C57B1/6 mice showed that the new 2-mercaptobenzimidazole derivative afobazole(1-100 mg/kg) prevented manifestations of the clastogenic effects of dioxidine (100 mg/kg, i.p.) over a period of 24 h and reduced by 44-75% the cytogenetic effect of dioxidine (300 mg/kg, i.p.). The same doses of afobazole produced a statistically significant decrease in the cyclophosphamide (20 mg/kg, i.p.) damage over a period of 24 h. Afobazole showed no inherent mutagen activity and did not potentiate the effects of mutagens studied.     

Antimutagenic hypoxen activity in vivo

The antimutagen effect of the drug hypoxen, representing poly(2,5-dihydroxyphenylene)-4-thiosulfonic acid sodium salt, was studied by chromosome aberration assay in the bone marrow cells of C57BL/6 mice. Hypoxen (20 mg/kg, i.p.) administered simultaneously with dioxidine (300 mg/kg, i.p.) reduced genotoxicity of the latter compound by 35% over a time period of 24 h. Preliminary five-day administration of hypoxen (70 mg/kg, p.o.) did not decrease the dioxidine damage. The genoprotector activity of hypoxen upon interaperitoneal injection is more pronounced as compared to that of the reference drug sladex (aspartam).     

Conditioned place preference after single doses or "binge" cocaine in C57BL/6J and 129/J mice

The rewarding effect of cocaine as reflected by the development of conditioned place preference was examined in C57BL/6J and 129/J mice. Cocaine was administered in a single daily dose (2.5, 5, 10 and 20 mg/kg ip) or in a "binge" pattern (15 mg/kg ip x3, hourly). Mice remained in the conditioning compartment for 30 min immediately after each injection. Single injections of cocaine from 5 to 20 mg/kg induced conditioned place preference in each strain of mice. Only C57BL/6J mice developed conditioned place preference after "binge" cocaine administration. Both strains showed significantly greater locomotion in the conditioning compartment across the range of single doses of cocaine and after "binge" cocaine administration, but only 129/J mice showed sensitization. When mice that had received the single 10 mg/kg dose were retested 4 weeks later, the amount of time spent in the preferred side was significantly reduced compared to the initial test in the 129/J, but not in C57BL/6J mice. Thus, the persistence of conditioned place preference is strain dependent. The fact that 129/J mice did not develop conditioned place preference after "binge" cocaine administration, but did after single doses, suggests that the rewarding effects of cocaine are influenced by pattern of administration, a factor that may be relevant to the development of human cocaine addiction.     

Effect of ketamine on exploratory behaviour in BALB/C and C57BL/6 mice

In this study, we evaluated the effect of ketamine on exploratory locomotion behaviours in the Balb/c and C57BL/6 strains of mice, which differ in their locomotion behaviours.Intraperitoneal administration of ketamine at three different doses (1, 5 or 10 mg/kg, 0.1 ml/10 gr body weight) was performed on adult male Balb/c and C57BL/6 mice. The same volume of saline was applied to the control group. The open-field and elevated plus maze apparatus were used to evaluate exploratory locomotion.In the open-field test, Balb/c mice less spend time in the centre of the field and was decreased locomotor activity compared to C57BL/6 mice (p < 0.01). Ketamine treatment of Balb/c mice at 10 mg/kg dose caused an increase in locomotor activity and an increase in the amount of time spent in the centre in the open-field test, compared to the control group (p < 0.05). In C57BL/6 mice, ketamine treatment (1 and 10 mg/kg) decreased locomotor activity (p < 0.05). In C57BL/6 mice, the three different doses of ketamine application each caused a decrease in the frequency of centre crossing (p < 0.001) and the spent time in the centre (p < 0.05).In the elevated plus maze, the number of open-arm entries, the percentage of open-arm time and total arm entries were decreased in Balb/c mice compared to C57BL/6 mice (p < 0.001). Ketamine treatment of Balb/c mice at 10 mg/kg dose caused an increase in the open-arm activity (p < 0.001). Ketamine application (10 mg/kg) decreased the open-arm activity in C57BL/6 mice (p < 0.05).A subanaesthetic dose of ketamine increased exploratory locomotion in Balb/c mice. In contrast, a subanaesthetic dose of ketamine decreased exploratory locomotion in C57BL/6 mice. In conclusion, hereditary factors may play an important role in ketamine-induced responses.     

Cocaine produces low dose locomotor depressant effects in mice

Cocaine produces several behavioral effects, most notably locomotor stimulation. Biochemically, cocaine is known to inhibit reuptake at the three monoamine transporter sites, and may have highest affinity at the serotonin transporter. Serotonin augmentation has been associated with decreases in behavioral activity, but cocaine has not been reported to produce behavioral depressant effects except at high doses which cause stereotypy and disruption of behavior. This study examined the effects of relatively low doses of cocaine, in the range of 0.1–10 mg/kg, on locomotor activity in C57BL/6J and DBA/2J mice. A biphasic dose-response curve was seen for both strains. At the lowest doses, activity was depressed. As the dose of cocaine increased, activity returned to baseline, and at the highest doses, increases in locomotor activity were found. DBA/2J mice were depressed at a lower dose of cocaine than were C57BL/6J mice; however, C57BL/6J mice showed locomotor depression over a broader range of doses. Activity was maximally depressed at 0.1 mg/kg for DBA/2J mice, and maximally depressed at 0.3 mg/kg for C57BL/6J mice. Thus, low doses of cocaine are shown to produce significant decreases in locomotor activity in two strains of mice. It is postulated that these low doses of cocaine which depress locomotor activity do so via inhibition of serotonin uptake, resulting in potentiation of serotonergic activity.     

Strain differences in the diabetogenic activity of streptozotocin in mice

We have already reported that slowly progressive non-insulin-dependent diabetes mellitus (NIDDM) is produced by a single i.p. injection of a subdiabetogenic dose (100 mg/kg) of streptozotocin (STZ) to 8-week-old male ICR mice. The aim of the present study was to clarify whether or not the progressive NIDDM is induced in ddY, BALB/c, C57BL/6 and ICR mice by the administration of STZ. Eight-week-old male mice of the 4 different strains were administered a single i.p. injection of STZ at various doses (ICR, ddY and BALB/c: 100-200 mg/kg; C57BL/6: 75-150 mg/kg). Among the ddY, BALB/c and C57BL/6 mice, a time course-related rise in non-fasting serum glucose levels throughout the observation period of 1-12 weeks after STZ administration was only induced in the 125 mg/kg STZ ddY and 100 mg/kg STZ ICR mice. In contrast with serum glucose levels, the area of islets and the percentage of the relative number of insulin-immunoreactive cells (beta-cells) to glucagon-immunoreactive cells (alpha-cells) in the 100 mg/kg STZ ICR and 125 mg/kg STZ ddY mice continued to decrease gradually over time. In addition, in low dose STZ mice of both strains, the insulin response to glucose stimulation was extremely impaired over time, although non-fasting serum insulin levels were maintained near normal levels. The rate of the progression of diabetes was faster in the 125 mg STZ ddY mice than in the 100 mg/kg STZ ICR mice.     

Inheritance of amphetamine-induced thermoregulatory responses in inbred mice

Two inbred strains of mice, DBA/2 and C57BL/6, differ in their responses to d-amphetamine-induced alteration of core temperature. At low doses of amphetamine (e.g., 2 mg/kg IP), both strains become markedly hypothermic within 10-20 minutes. High doses (e.g., 20 mg/kg IP) induce significant hyperthermia (+1.8 degrees C) in DBA/2 mice but have only a slight hyperthermic effect (+0.2-0.3 degrees C) effect on C57BL/6 mice. The phenotype of the F1 hybrid strain derived by crossing C57BL/6 by DBA/2 is indistinguishable from its C57BL/6 parent at a dose of 20 mg/kg IP, i.e., reduced responsiveness to amphetamine-induced hyperthermia is dominant. Analysis of the thermoregulatory responses of recombinant inbred derivatives (lines BXD-9, 11, 15, 19, 20, 21, 23, 27, 28, 30) suggest that the relative responses to amphetamine-induced hyperthermia is inherited in a simple Mendelian fashion. These results differ from other pairs of inbred mouse strains which have been compared. These findings identify yet another neuropharmacological difference between mouse strains C57BL/6 and DBA/2 and are reviewed in terms of neuroregulatory mechanisms effecting thermoregulation.     

Discrimination and self-administration of nicotine by inbred strains of mice

These studies aim to characterize the discriminative stimulus effects of nicotine in two inbred strains of mice that differ in many pharmacological responses, and to investigate the feasibility of IV self-administration studies with nicotine in one of the strains. For discrimination studies, three groups of C57BL/6 and one group of DBA/2 mice were trained in a two-lever operant conditioning paradigm with a tandem VI-30″ FR-10 schedule of food reinforcement. After 40 training sessions, accuracy reached 57.5, 77.5 and 90.0% in C57BL/6 mice trained with (–)-nicotine (SC) in doses of 0.4, 0.8 and 1.6 mg/kg, respectively (n = 8). DBA/2 mice trained with 0.8 mg/kg nicotine attained similar (73.3%) accuracy (n = 9). Results from extinction tests showed that all groups of mice yielded orderly dose-response curves for nicotine (0.03–1.6 mg/kg), but stimulus control remained notably weaker for the mice trained with 0.4 mg/kg nicotine than for any other group. Overall rates of responding in the undrugged state were lower for DBA/2 than for C57BL/6 mice; DBA/2 mice were also slightly less sensitive than C57BL/6 mice to the response rate-reducing effect of nicotine. The nicotine antagonist mecamylamine (1.5 mg/kg SC) blocked the discriminative stimulus effect of the training dose of nicotine in all groups. The results of the IV self-administration study suggest that nicotine (0.1 mg/kg) can serve as a positive reinforcer in drug–naive C57BL/6J mice (n = 13). Behaviour maintained by 0.1 mg/kg nicotine injections was significantly greater than behaviour maintained by vehicle injections, and it was maintained under an intermittent schedule of reinforcement (FR4). The methods described provide possible approaches for genetic analyses of strain differences in sensitivity to the discriminative and reinforcing stimulus properties of nicotine. Received: 11 April 1998/Final version: 28 June 1998     

The effects of fexofenadine on eosinophilia and systemic anaphylaxis in mice infected with Trichinella spiralis

BACKGROUND: The effects of the non-impairing, H(1)-receptor antagonist fexofenadine were investigated in in vivo mouse models of eosinophilia and systemic anaphylaxis. METHODS: Eosinophilia was investigated in C57BL/6 mice (n=5 per group) infected with Trichinella spiralis, with and without administration of fexofenadine HCl (5, 10 and 20 mg/kg/day). Eosinophilia was also studied, with and without fexofenadine administration, in mice with a congenital mast-cell deficiency (W/W(v)) and controls (+/+). The effect of fexofenadine HCl (20 mg/kg/day) on IL-5 and eotaxin blood levels was also investigated in C57BL/6 mice. In a separate model, systemic anaphylaxis was induced in C57BL/6 mice using T. spiralis antigen. Fexofenadine HCl (5, 10 and 20 mg/kg) or vehicle was administered 20 min before antigen challenge (n=5 per group). The effect of fexofenadine on systemic anaphylaxis caused by IgE and anti-IgE was also examined in CBF1 mice injected with serum from NC/Nga mice with high IgE levels. Rectal temperature was measured as an indicator of anaphylaxis. RESULTS: In C57BL/6 mice, repetitive oral administration of fexofenadine HCl (5, 10 and 20 mg/kg/day) resulted in dose-dependent suppression of eosinophilia (p<0.05-0.0001). No suppression was observed in mast-cell deficient W/W(v) mice. In addition, single oral administration of fexofenadine HCl (10 and 20 mg/kg) significantly suppressed the decrease in rectal temperature (p<0.01), a marker for systemic anaphylaxis, in C57BL/6 mice. In CBF1 mice injected with serum from NC/Nga mice with high IgE levels, the decrease in rectal temperature was suppressed by single administration of fexofenadine HCl (10 and 20 mg/kg; p<0.01 and p<0.001, respectively). Fexofenadine had no effect on peripheral IL-5 and eotaxin levels. CONCLUSION: These results indicate that fexofenadine suppresses both eosinophilia and systemic anaphylaxis, both of which are fundamental reactions in allergic diseases.     

Induction of cytosolic and microsomal epoxide hydrolases by the hypolipidaemic compound nafenopin in the mouse liver

The repeated oral administration of nafenopin, a hypolipidaemic compound, at a dose of 100 mg/kg to male C57BL/6, DBA/2, Balb c and C3H mice caused an increase in the specific activity of liver cytosolic epoxide hydrolase, the activity of microsomal epoxide hydrolase was also increased in all except the C3H mice. The dose dependence and the specificity of this induction was investigated in male DBA/2 mice. In the range of 10-200 mg/kg nafenopin the induction of the two hydrolase activities was found to increase with increasing doses of the test compound. Two other cytosolic enzyme activities, lactate dehydrogenase and glutathione S-transferase, remained essentially unchanged within the dose range investigated.     

Reverse tolerance to ambulation-increasing effects of methamphetamine and morphine in 6 mouse strains

Effects of single administration of methamphetamine (1, 2 and 4 mg/kg, s.c.) and morphine (5, 10 and 20 mg/kg, s.c.) and repeated administration of methamphetamine (2 mg/kg, s.c.) and morphine (10 mg/kg, s.c.) on ambulatory activity were investigated in 6 mouse strains: dd, ICR, BALB/c, C57BL/6, C3H/He and DBA/2. Although there were differences in the drug sensitivities among mouse strains, methamphetamine and morphine increased the ambulatory activity in all the strains except for the DBA/2 strain that showed an increase only after morphine. Repeated 5 times administration of methamphetamine at intervals of 3-4 days induced a reverse tolerance (an enhancement in the sensitivity) to the ambulation-increasing effect in all the strains with a marked degree in dd, ICR, C3H/He and DBA/2 strains and a slight degree in BALB/c and C57BL/6 strains. The same treatment with morphine induced reverse tolerance to the effect of morphine markedly in C57BL/6 and C3H/He strains and moderately in dd, ICR and BALB/c strains, but the DBA/2 strain showed no significant change in the ambulatory activity throughout the repeated 5 times administration of morphine. There was positive correlation between the initial drug sensitivities of animals and the degrees of the reverse tolerance in either methamphetamine or morphine. Furthermore, the reverse tolerance to methamphetamine and morphine was sometimes transferable, although such cross interaction varied among mouse strains.     

The effects of intraperitoneal administration of the GABA(B) receptor agonist baclofen on food intake in CFLP and C57BL/6 mice

The effects of the GABA(B) receptor agonist baclofen were investigated on food intake in non-deprived CFLP and C57BL/6 mice. In Experiment 1, baclofen (1-8 mg /kg) administered i.p. to CFLP mice, produced a dose-related increase in food intake. The 4 and 8 mg/kg doses produced significant increases in cumulative feeding when measure 120 min after administration (at least P < 0.05, in each case). In Experiment 2, baclofen (1-10 mg/kg), administered intraperitoneally (i.p.) to C57BL/6 mice, also produced a dose-related increase in food intake. The 4 mg/kg dose of baclofen significantly increased cumulative food intake at 60 min (P < 0.05), while the 2 and 4 mg/kg doses significantly increased cumulative food intake at 120 min (P < 0.01, in each case). The 10mg/kg dose was without effect. These data show that systemic administration of the GABA(B) agonist baclofen produces an increase in food consumption in two different strains of mice and extend previous observations made in rat to another rodent species.     

Behavioral effects of trimethyltin in two strains of mice. I. Spontaneous motor activity

Adult male mice (C57BL/6N and BALB/c) were administered single doses of trimethyltin X Cl (TMT) by the ip route. The effects of TMT administration were determined on lethality (3-6 mg/kg), spontaneous motor activity (SMA), and the physical appearance of the mice (0.3-3 mg/kg). The effects of TMT on lethality were strain dependent in that a single dose of 3 mg/kg, ip, produced approximately 35% lethality in the C57BL/6N strain during the first 72 hr following administration. Less than 15% lethality was observed at this dose in the BALB/c strain. In both strains, 3.5 mg/kg, ip, produced more than 70% lethality during the first 144 hr after administration. Higher doses produced proportionally greater lethality. The SMA of both strains was not affected significantly at doses below 1 mg/kg, ip. At 1 mg/kg a small decrease in activity was observed during the first 24 hr. At 3 mg/kg, SMA was initially decreased in both strains. However, the decrease was of smaller magnitude in the C57BL strain and was followed by a large increase in SMA which did not return to control levels for approximately 1 week. An increase in SMA was observed in the BALB/c strain on the fifth day following TMT but returned to control values by Day 6. At 3 mg/kg, ip, the C57BL mice were observed to have severe whole body tremors and were hypersensitive to external stimuli. The whole body tremor was not as marked in the BALB/c strain. Neuropathological studies on the treated mice indicated that the behavioral studies paralleled the pathology produced by TMT. These data confirm the initial observation of greater sensitivity of the mouse to toxic effects of TMT compared to the rat.     

Chronic nicotine-induced changes in dopaminergic system: effect on behavioral response to dopamine agonist.

The effect of chronic nicotine on dopamine-agonist-mediated locomotor activity response was measured in BALB/cBy and C57BL/6 mice. Mice were injected twice daily for 10 days with 1.2 mg/kg SC (-)-nicotine di-(+)tartrate. Subsequent locomotor activity response to apomorphine (1 mg/kg SC) was measured. Apomorphine induced hypomotility in both strains of mice, with the BALB/cBy mice showing a greater hypomotility compared to the C57BL/6 mice. The response to apomorphine was attenuated in both strains of mice that were treated previously with repeated injections of nicotine. The results suggest that chronic nicotine may induce changes in the dopaminergic system, which is reflected in altered behavioral response to a dopamine agonist.     

Strain differences in the reverse tolerance to methamphetamine and changes in catecholaminergic neurons in mice

The effect of methamphetamine (MAP) on ambulatory activity and neurochemical changes in catecholaminergic neurons in the brain were investigated in dd and C57BL/6 strains of male mice. The mice were given repeatedly MAP at 2 mg/kg, s.c., 10 times at a fixed interval of 4 days. Single MAP markedly increased the ambulatory activity in both strains of mice. The ambulation-increasing effect was progressively enhanced without accompanying stereotyped behaviors when the drug was repeatedly given. The dd mice showed higher susceptibility not only to single MAP but also to the enhancing effect of the drug (reverse tolerance) that the C57BL/6 mice. On the other hand, non-treated dd mice exhibited lower maximum densities of 3H-spiperone binding sites in the striatum and 3H-WB4101 binding sites in the cortex and hippocampus than non-treated C57BL/6 mice. In contrast, the dd mice exhibited higher noradrenaline turnover than the C57BL/6 mice in the brain regions examined. The repeated administration of MAP produced decrease in the densities of both 3H-spiperone and 3H-WB4101 binding sites in the corresponding regions with increase in catecholamine turnover in dd mice. However, the similar changes were observed only in 3H-WB4101 binding sites and noradrenaline turnover in C57BL/6 mice. These results suggest that the ambulation-increasing effect of MAP is positively correlated with catecholamine turnover, while it was correlated negatively with the densities of catecholamine binding sites. Furthermore, the enhancing effect of MAP is supposed to have been partially elicited by changes in brain catecholaminergic systems, in particular an increase in catecholamine turnover.(ABSTRACT TRUNCATED AT 250 WORDS)     

烟酰胺单核苷酸对内毒素休克小鼠死亡率的影响

目的 探究烟酰胺单核苷酸(NMN)对脂多糖(LPS)诱导的内毒素休克小鼠死亡率的影响.方法 将10周龄C57BL/6J雄性小鼠随机分组,均腹腔注射LPS(10 mg/kg)造模.NMN腹腔注射给药,分为3种方式:①造模后0.5 h给药,剂量为10、30、100、300 mg/kg;②造模前0.5 h给药,剂量为30、1...     

Flumazenil induces benzodiazepine partial agonist-like effects in BALB/c but not C57BL/6 mice

Rationale: Some anxiety disorders may be treated in a different way than normal anxiety. Objective: This study was aimed at investigating the action of the benzodiazepine receptor antagonist flumazenil, compared to that of the benzodiazepine receptor full agonist chlordiazepoxide, in an animal model of generalised anxiety disorder (the BALB/c mouse). Methods: Flumazenil (0.0001, 0.001, 0.01, 0.1 and 1 mg/kg) or chlordiazepoxide (5 mg/kg) were administered to BALB/c or C57BL/6 mice subjected to the light/dark test, the elevated plus maze or a passive avoidance step-through paradigm. Results: Chlordiazepoxide and flumazenil (at all doses tested in the elevated plus maze and at the doses of 0.001 and 0.01 mg/kg in the light/dark test) induced a strong anxiolytic effect in BALB/c mice. Flumazenil did not induce anxiolysis in C57BL/6 mice, whatever the behavioral test or the dose used. However, chlordiazepoxide elicited anxiolysis in this strain in both procedures. In the passive avoidance test, chlordiazepoxide was amnesic in both strains but flumazenil had no effect. Conclusion: Flumazenil induces partial agonist-like effects in BALB/c and not in C57BL/6 mice, suggesting a possible benzodiazepine receptor set point shift toward the agonistic direction in some pathological anxiety states such as generalised anxiety disorder. Received: 23 January 1999 / Final version: 26 June 1999     

The effect of disodium 4-chloro-2-iminodibenzoate (CCA) on IgE levels and anaphylactic shock

The effect of disodium 4-chloro-2,2-iminodibenzoate (CCA) on IgE antibody response was examined in C3H/A and (BALB/c x C57BL/6J) F1 hybrid mice immunized with low doses of ovalbumin (OA) adsorbed on aluminium hydroxide gel. CCA administered orally at the doses of 5 and 50 mg/kg/day reduced IgE antibody production in these mice as determined by PCA test. High doses of CCA (100 mg/kg/day) given from day 7 before immunization of C57BL mice and during 1 week after immunization of mice with OA and Bordetella Pertussis Vaccine reduced the mortality of these mice subjected to anaphylactic shock on day 7 of immunization. CCA treatment was ineffective in anaphylactic shock of C57BL mice immunized with very high dose of OA, known to elicit little or no IgE antibody production but high IgG antibody response. The treatment of OA-immunized Guinea pigs with one oral dose of CCA (100 mg/kg) did not reduce mortality in protracted anaphylactic shock. Our results demonstrate that CCA inhibits IgE production as well as IgE mediated hypersensitivity reactions in mice.