Ethanol intoxication and withdrawal among three age groups of C57BL/6NNIA mice

Data have not been forthcoming on the effects of chronic ethanol administration on intoxication and severity of withdrawal using animals representative of the life-span of a particular species. The purpose of this study was to examine ethanol intoxication and withdrawal among three age groups (3, 14, 25 months) of C57BL/6NNIA male mice. Ethanol was administered in a liquid diet for 14 days. Pair-fed control groups and laboratory chow groups were also employed. Blood ethanol levels, signs of intoxication and withdrawal, liquid diet consumption, and body weight were measured. Old mice were significantly more intoxicated than younger mice. However, young mice consumed more ethanol as compared to the older mice. Blood ethanol levels did not differ among the three age groups, although variability was high within each age group. The ethanol liquid diet groups did not show a decrease in body weight. Withdrawal was more severe for old animals than younger animals. The greater effects of ethanol observed in the old animals do not appear to be attributable to age differences in blood ethanol levels, amount of ethanol consumed, or body weight loss.     

Effects of pre- and post-trial caffeine administrations on simultaneous visual discrimination in three inbred strains of mice

BALB/cJ, DBA/2J, and C57BL/6J mice were injected with caffeine and tested, in the five choice Yerkes-Thompson Bryant-Bovet Nitti apparatus for patterns discrimination, in two sets of experiments. In the first the patterns were opposite oriented oblique bars, in the second U-shaped figures, one opened toward the right, the other toward the left.As concerns the saline injected animals in both sets of experiments, the BALB mice showed the highest learning abilities; in the second set the C57 strain, whose performance had not been different from that of the DBA mice in the first set, performed at the lowest level.Pre- and post-trial caffeine (5 mg/kg) administrations were followed by performance impairment in the BALB strain, while performance improvements were evident in the drugged animals belonging to the other two strains.     

Effects of heroin,alone or in combination with other drugs,on the locomotor activity in two inbred strains of mice

The locomotor activity of C57B1/6J and DBA/2J mice was studied, under the influences of heroin, amphetamine, strychnine, or ethanol, and of combinations of the opiate with each one of the other drugs. Heroin treatment was followed by the typical running fit in the C57 mice, while the DBA strain was unaffected. Amphetamine enhanced the activity in the C57 strain only. The combination of heroin with amphetamine or ethanol increased the locomotor activity only in the DBA strain, while heroin + strychnine exerted a clear stimulating effect on the activity of the C57 mice. The strychnine + heroin mixture was more toxic than heroin alone when the lethal doses (LD50) were determined in the 2 strains.     

Dose-dependent effects of heroin on memory in two inbred strains of mice

Heroin was administered to DBA/2 and C57BL/6 mice, trained in the five-choice Yerkes-Thompson-Bryant-Bovet-Nitti apparatus for pattern discrimination, in two sets of experiments. In a first set, pretrial administrations of heroin (0.1, 0.25, or 0.5 mg/kg) improved performance in both strains. In a second set, heroin (0.5 mg/kg) immediately following each training session were followed by performance improvements in both strains, while the performance of C57 mice was improved and that of the DBA mice was impaired by 5 mg/kg of opiate. No effect was evident in this set of experiments when heroin was injected 2 h after each session, suggesting that effects of the pretrial treatments were due to influences of the opiate on the consolidation processes of the strains tested.     

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.     

Alcohol-induced locomotor activation in C57BL/6J, A/J, and AXB/BXA recombinant inbred mice: strain distribution patterns and quantitative trait loci analysis

RATIONALE: Quantitative trait loci (QTLs) for initial sensitivity to alcohol have been identified in a number of mouse strains (e.g. BXD); however, confirmation is required. OBJECTIVES: The present paper aimed to characterize the C57BL/6J, A/J, and AXB/BXA recombinant inbred (RI) strains of mice for basal and ethanol-induced locomotor activation as measured in an open field and to provide provisional location of QTLs for these phenotypes. METHODS: A/J and C57BL/6J mice were habituated to handling and then randomly assigned to receive one of four alcohol doses (0, 0.5, 1.0, 2.0 g/kg). Subsequently, all available strains of the AXB/BXA RI were tested with the 2 g/kg dose of ethanol or vehicle control. RESULTS: Simple regression and interval mapping were used initially to identify significant gene markers associated with ethanol-induced activation (calculated as total activity on alcohol day-total activity on saline day). Subsequently, composite interval mapping (CIM) was used to increase the accuracy in mapping individual loci. Genetic markers on chromosomes 2, 3, 8, 13, 16, 18 and 19 were associated with ethanol-induced activation. CONCLUSIONS: Three significant markers identified through CIM accounted for 86% of the genetic variance in the ethanol-induced activation. QTLs on chromosome 16 (45.6 cM) and 19 (24 cM) previously associated with alcohol consumption in the AXB/BXA RI mice were found to overlap with QTLs for ethanol-induced activation identified in the present study.     

Different effects of apomorphine on climbing behavior and locomotor activity in three strains of mice

Apomorphine (0.1, 0.25, 0.5, 1, 3 mg/kg, SC), induces a dose-dependent reduction of locomotor activity in DBA/2(DBA) and BALB/c(BALB) mice, while it enhances locomotor activity in a biphasic way in C57BL/6(C57) mice. On the other hand, apomorphine is ineffective in modifying climbing behavior in DBA mice while it increases climbing behavior in C57 and BALB mice. The results, taken together, suggest that these are two different behaviors, possibly controlled by different dopaminergic mechanisms depending on the genetic makeup.     

Differences in learning and extinction in response to vasopressin in six inbred mouse strains

Vasopressin was found to enhance acquisition of conditioned avoidance responses in one inbred mouse strain and to retard extinction; in another inbred mouse strain vasopressin depressed the acquisition of conditioned avoidance; in four additional inbred mouse strains vasopressin had no effect on conditioned avoidance learning.     

Voluntary consumption of ethanol in 15 inbred mouse strains

To determine genetic differences in ethanol consumption, 15 commonly used inbred strains of mice were given ad libitum two-bottle choice between ethanol, 0.2% saccharin, or ethanol plus saccharin in one bottle versus tap water in the other bottle. Three different concentrations of ethanol were used: 3%, 6% and 10% (v/v). Of the 15 strains, the C57BL/6J, C57BR/cdJ and C57L/J strains showed the most consistent higher intake of ethanol either with or without 0.2% saccharin. In marked contrast, the DBA/1J and DBA/2J strains consistently showed the lowest intake. Consumption of 3% ethanol without saccharin was highly genetically correlated with saccharin consumption (r=0.77), suggesting that low concentrations of ethanol may have a sweet taste that affects voluntary consumption. Most strains showed very different patterns of response to ethanol with or without saccharin. Three patterns of strain responses were identified. Some strains avoided higher concentrations of ethanol whether in water or saccharin; some appeared to be sensitive to the ability of saccharin to mask the odor of ethanol; and some may have reduced consumption only when ethanol concentrations were high enough to produce aversive postingestional effects. Whereas earlier studies generally attempted to explain strain differences in consumption by invoking a single mechanism, our results demonstrate that more than one mechanism is necessary to explain the preferential ethanol intake of all strains studied.     

Effects of chlorpromazine and imipramine on discrimination learning,consolidation, and learned behavior in two inbred strains of mice

Chlorpromazine and imipramine were administered to DBA/2J and C57BL/6J mice swimming in a Y water maze toward a light source (L Procedure, corresponding to innate tendency) or towards the dark (D Procedure, sorresponding to the acquisition of a new pattern of behavior). In two sets of experiments the drugs were administered to naive mice before and after each training session, respectively.In both strains, in the pretrial experiments, the innate tendencies were improved by both drugs; the acquisition of a new pattern of behavior was improved following imipramine but impaired following chlorpromazine. In the posttrial experiments (D procedure) the consolidation processes of both strains were improved following imipramine and impaired following chlorpromazine.In a third set of experiments imipramine was administered to previously trained mice of both strains and chlorpromazine to previously trained C57 mice. In both procedures the administration of increasing doses of both drugs was followed by a progressive lengthtening of the swimming times in the previously trained C57 mice; performance disruptions were evident in both procedures in trained DBA mice following imipramine.     

Effects of mescaline and psilocin on acquisition,consolidation, and performance of light-dark discrimination in two inbred strains of mice

Mescaline and psilocin were administered to DBA/2J and C57B1/6J mice swimming in a Y water maze toward a light source (L Procedure, corresponding to innate tendency), or toward the dark (D Procedure, corresponding to the acquisition of a new pattern of behavior). In two sets of experiments the hallucinogens were administered to naive mice before and after each training session, respectively.In the pretrial experiments, the innate tendencies of both strains were improved by both mescaline and psilocin administrations. This effect was similar to that observed in previous investigations following nicotine, chlorpromazine, imipramine, and (for the DBA mice) amphetamine administrations. The acquisition of a new pattern of behavior was improved by the hallucinogens in the C57 mice and impaired in the DBA mice. Opposite effects in the two strains (improvement for the C57, and impairment for the DBA strain) were observed when mescaline, or psilocin, was injected immediately (not 2h) after each training session (D Procedure). These effects were similar to those observed following nicotine administrations in previous studies.In a third set of experiments, mescaline was administered to C57 and psilocin to both C57 and DBA mice previously trained in L or D procedure. The administration of both hallucinogens was ineffective in the C57 strain, while performance disruptions, as previously observed with mescaline, were evident following psilocin in the DBA mice previously trained to swim toward the dark.     

Genetic effects on PCP-induced stimulation in recombinant inbred strains of mice

The stimulation of motor activity by phencyclidine was found to differ significantly in BALB/c and C57B1/6By inbred strains of mice. Phencyclidene-induced stimulation was compared for these strains, their reciprocal F1 hybrids, and their recombinant inbred offspring. There were significant differences in responsitivity among the strains, suggesting a genetic influence on the PCP response; however, the strains did not segregate into two distinct groupings, suggesting that this genetic influence was not carried by a single gene. In addition, there was no relationship between the responsitivity of these strains of mice to PCP and their previously-reported responses to amphetamine or scopolamine, which suggests that PCP-induced stimulation is not a simple cholinergic or amphetamine-like response.     

Strain dependent effects of ketamine on locomotor activity and antinociception in mice

The effects of ketamine (12.5, 25 and 50 mg/kg) on locomotor activity and response to nociceptive stimuli were investigated in the inbred strains of mice: BALB/c (BALB), C57BL/6 (C57) and DBA/2 (DBA). In the BALB and in the C57 mice ketamine exerted activity stimulating effects, which were already present at doses lower than those inducing antinociception. Locomotor depressant effects were evident in the DBA mice following the administration of doses higher than those necessary to induce analgesia. It is suggested that: (1) ketamine affects locomotor activity and response to painful stimuli through different mechanisms, (2) the brain regional and biochemical differences reported for the strains considered may account for their different responses to ketamine administration.     

Parametric and pharmacological modulations of latent inhibition in mouse inbred strains

Latent inhibition (LI) is a cross species selective attention phenomenon, which is disrupted by amphetamine and enhanced by antipsychotic drugs (APDs). Accumulating data of LI in gene-modified mice as well as in mouse inbred strains suggest genetic component of LI. Here we study modulation of LI in mouse inbred strains with spontaneously disrupted LI by parametric manipulations (number of pre-exposures and conditioning trials) and pharmacological treatments with antipsychotics and NMDA modulator, D-serine. C3H/He and CBA/J inbred mice showed disrupted LI under conditions with 40 pre-exposures (PE) and 2 trials of the conditioned stimulus-unconditioned stimulus (CS-US) due to either loss of the pre-exposure effect or a ceiling effect of poor learning, respectively. The increased number of pre-exposures and/or number of conditioning trials corrected expression of LI in these inbred mice. The disrupted LI was also reversed by haloperidol in both inbred strains at 1.2 mg/kg but not at 0.4 mg/kg, as well as by clozapine (at 3 mg/kg in C3H/He and at 9 mg/kg in CBA/J mice). D-serine potentiated LI in C3H/He mice at 600 mg/kg, but not in the CBA/J at both studied doses (600 and 1800 mg/kg). Desipramine (10 mg/kg) had no effect on LI in both inbred mouse strains. Our findings demonstrated some resemblance between the effects of parametric and pharmacological manipulations on LI, suggesting that APDs may affect the capacity of the brain processes environmental stimuli in LI. Taken together, LI may offer a translational strategy that allows prediction of drug efficacy for cognitive impairments in schizophrenia.     

Increased sensitivity to chronic ethanol in isolated mice

Isolated C57BL/10 mice fed liquid diet as their only nutritional supply consumed 44% more diet than did groupedhoused mice. A similar increase due to isolation of 36% for C57BL/10 mice and of 89% for DBA/1 mice was demonstrated when the sucrose in the liquid diet was replaced by an equicaloric (6% v/v) amount of ethanol. The ethanol-drinking isolated mice suffered a higher mortality rate than the grouped mice. When isolated mice were given a restricted amount of ethanol diet to match the consumption of the grouped mice, their death rate still remained higher. It was concluded that isolation increased the sensitivity to ethanol effects. The observed changes in the sensitivity to ethanol effects may have been mediated by the known isolation-induced changes in the levels of brain amines and corticosterone. Generally, DBA/1 mice were more susceptible to chronic ethanol than C57BL/10, and the young more susceptible than the adults.     

A single gene difference determines relative susceptibility to caffeine-induced lethality in SWR and CBA inbred mice

Inbred mouse strains SWR and CBA differ markedly in their relatively susceptibility to the acute toxic effects of intraperitoneally administered caffeine. At a dose of 187 mg/kg, SWR mice survive a stress-potentiated lethality test apparently related to the generation of tonic seizures; in contrast, CBA mice usually die in less than 30 seconds after this dose. Progeny from several different genetic crosses were characterized to determine the genetic basis underlying this phenotypic difference in caffeine sensitivity. F1 progeny from reciprocal crosses of the parental strains were uniformly sensitive to caffeine-induced lethality, i.e., caffeine responsiveness behaves like an autosomal dominant trait. Self-crossing of F1 individuals produced both progeny which were resistant to caffeine-induced lethality (26% of the total) and those which were susceptible (74%). Backcrosses of the F1 animals to the CBA parent produced no (0/19) resistant progeny. In contrast, backcrosses of F1 animals to SWR produced 54% resistant progeny. These data indicate that the difference in susceptibility to caffeine-induced lethality between these strains is determined by a single pair of autosomal alleles in which susceptibility (responsiveness) to this methylxanthine is dominant to resistance (nonresponsiveness).     

Fixed-ratio schedules of oral ethanol self-administration in inbred mouse strains

Previous studies of ethanol reinforcement in BALB/cJ and C57BL/6J mice have shown that over a range of concentrations oral ethanol appeared to serve as a reinforcer only for the C57BL/6J mice. In the previous studies BALB/cJ mice maintained rates of responding for ethanol that only slightly exceeded the rates maintained by the vehicle, water. However, the quantity of ethanol consumed with the continuous reinforcement schedule (fixed ratio one) may have led to pharmacologically significant effects, given the high sensitivity to ethanol of this genotype. The present study tested whether and to what extent ethanol would maintain responding under increasing fixed ratio size in these two strains of mice at ethanol concentrations of 0%, 8%, and 16% (w/v). For the C57BL/6J mice, as fixed-ratio size increased from 1 to 2, 4, and 8, there were almost directly proportional increases in response rate at ethanol concentrations of 8% and 16% (w/v), but not at 0%. Post-session blood ethanol levels confirmed intake of pharmacologically significant quantities. The volume consumed per unit of body weight decreased as fixed-ratio size increased. For the BALB/cJ mice, at no condition did ethanol maintain responding at levels that significantly exceeded vehicle maintained responding. BALB/cJ mice did not differ from C57BL/6J mice as fixed-ratio size was increased during vehicle conditions. These results, along with earlier findings, demonstrate that ethanol can serve as a reinforcer for C57BL/6J mice but not in BALB/cJ mice over a range of schedule conditions. They further support the conclusion that genotype is an important determinant of ethanol reinforced behavior.     

γ-Aminobutyric acid in brain areas of isolated aggressive or non-aggressive inbred strains of mice

In order to investigate the effects of social isolation on aggressive behavior and GABA levels in different brain areas, inbred mice of the C57 B1/6 and the DBA/2 strains were housed inidividually over a period of 8 weeks. Social isolation induced a clear increase of aggressive responses only in the DBA/2 strain and a decrease of GABA levels in septum, striatum, olfactory bulb and posterior colliculus in both the C57B1/6 and in the DBA/2 strains. An increase of neurotransmitter concentration was observed in amygdala of DBA mice. DBA mice when compared when compared to C57 mice showed significantly lower levels of GABA in olfactory bulb and striatum. These results are discussed in light of several previous studies which have pointed out a correlation between a deficiency of GABA mediated inhibition in some brain areas and different kinds of aggressive behavior as well as the possibility of blockade of aggressive behavior by potentiation of GABAergic mediated inhibition. A possible suggestion emerging from our results is that the aggressive responses exhibited by isolated DBA mice but not by isolated C57 mice may be related to lower levels of the inhibitory neurotransmitter in the olfactory bulb and striatum.     

Behavioural effects of (-)naloxone in mice from four inbred strains

To study the role of endogenous opioid peptides in the regulation of behavioural responses to novelty, male mice from the inbred strains SRH, SRL, C57BL/6, and DBA/2 were injected IP with either saline alone, or the opiate antagonist naloxone, dissolved in saline, in dosages of 4 or 8 mg/kg. After 10 min, the animals were placed individually for 20 min in a novel environment and some 12 behavioural components were recorded. Naloxone reduced grooming and incipient rearing in all four strains and it reduced sniffing, leaning against the wall, and locomotor activity in some of them. Object-sniffing, object-leaning, defecation, freezing, and Straub tail elevation remained unaffected. The results for grooming and locomotor activity are largely in agreement with reports from others. Rather unexpectedly, the drug enhanced rearing responses in all strains. Although in several cases, a genotype-treatment interaction became apparent, the observed strain differences usually persisted and the correlations found between the behavioural components did not alter much. The naloxone-induced reductions in sniffing, leaning, locomotion, and grooming suggest endogenous opioid involvement in the control of behavioural activation in a novel situation. The increases in rearing possibly result from an additional agonist action of naloxone.     

CXCL5基因敲除小鼠的繁殖、基因型鉴定及与野生型小鼠的比较

目的：繁殖和鉴定 CXC 趋化因子配体5（CXC chemokine ligand 5,CXCL5）基因敲除小鼠,以获得 CXCL5－／－纯合子小鼠并与野生型小鼠进行比较。方法将 CXCL5＋／－杂合子小鼠繁殖后,剪取子代小鼠耳组织,提取基因组 DNA ,用 PCR 法鉴定子代小鼠的基因型。采用独立样本 t 检验比较同周龄同性别 CXCL5基因敲除纯合子小鼠与野生型小鼠的体重和结直肠长度,并通过苏木素‐伊红染色观察两种基因型小鼠的结肠形态结构。结果经繁殖,共获得60只 CXCL5－／－纯合子小鼠和55只野生型小鼠。4、6、8、10周龄雌性 CXCL5－／－小鼠的体重分别为（10．08±0．78）、（14．55±0．92）、（18．01±0．68）和（19．75±1．23） g ,明显轻于同龄雌性野生型小鼠〔（11．43±0．85）、（18．42±0．76）、（20．42±1．63）和（21．27±1．66） g〕（t 值分别为‐2．622、‐7．253、‐3．042、‐1．644,P 值均＜0．05）;6、8周龄雄性CXCL5－／－小鼠的体重分别为（17．46±0．74）和（20．62±1．62） g ,也明显轻于同龄雄性野生型小鼠〔（20．47±1．66）和（23．33±1．67）g〕（t 值分别为3．688、2．885,P 值均＜0．05）。6周龄雌性CXCL5－／－小鼠的结直肠长度为（6．86±0．17） cm ,与同龄雌性野生型小鼠（7．66±0．11） cm 的长度相比,明显较短（t＝8．835,P ＜0．05）,但结肠的形态结构无明显改变。结论成功获得了 CXCL5基因敲除纯合子小鼠,为深入研究 CXCL5的生物学功能奠定了基础。