The influence of mouse genotype on the changes in brain cyclic nucleotide levels induced by acute alcohol administration.

Two mouse strains (C57BL/6By and BALB/cByJ) were found to differ widely in their sleep-time response to ethanol (3 g/kg), but showed no difference in their hypothermic response to the same ethanol dose. Comparison of brain cyclic nucleotide levels in the two strains revealed a strain difference in the brain cyclic AMP response to ethanol but no strain difference in the magnitude of the brain cyclic GMP change. Alcohol produced a significant drop in cerebellar cyclic GMP in both strains, and a decrease in cerebellar cyclic AMP in C57BL/6By mice. The cyclic AMP/cyclic GMP ratio increased following alcohol in the cerebellum of BALB/cByJ mice but not C57BL/6By mice. The results are discussed in terms of possible relationships between alcohol-induced changes in neurochemistry and behavior.     

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.     

Genotype-dependent modulation of LY 171555-induced defensive behavior in the mouse

The selective D2 dopamine receptor agonist LY 171555 increased defensive behavior dose dependently, decreased social investigation and activity, and increased immobility in mice of the C57BL/6 (C57) strain interacting with non-aggressive mice of the seme strain. In the same test situation, DBA/2 (DBA) mice did not present any increase in defensive behavior following injection of the same doses of LY 171555, while exhibiting a marked decrease in activity and increased immobility. Mice of the BALB/c strain were less responsive than C57 mice as far as defensive behavior was concerned, and showed decreased activity and social investigation and increased immobility. These results point to a major genetic role in the modulation of social behavior by D2 receptors.     

An analysis of cocaine effects on locomotor activities and heart rate in four inbred mouse strains

The effects of cocaine on Y-maze activity and heart rate have been examined in four inbred strains of mouse (BALB, C57BL, C3H and DBA). In addition, brain [3H]-cocaine concentrations were measured at the time of maximal response to cocaine. Cocaine produced a dose-related increase in Y-maze cross activity in C3H, DBA and C57BL, with C3H mice being considerably more sensitive than DBA or C57BL. Cocaine was without effect on Y-maze cross activity in BALB mice. Cocaine produced a biphasic effect on rearing activity in C3H mice, a dose related depression in BALB mice, and was without effect on C57BL and DBA mice. At the highest dose studied (15 mg/kg), cocaine produced a small decrease in heart rate in C3H mice. Strain differences in behavior were maximal 15 minutes after a dose of 5 mg/kg, IP. At this dose and time interval, brain [3H]-cocaine concentrations were not significantly different among the four strains of mice. The results suggest a genetically-determined difference in CNS sensitivity to cocaine.     

Genetic differences in the locomotor response to single and daily doses of phencyclidine in inbred mouse strains

Genetic differences in the locomotor stimulant effects of both single and daily administration of phencyclidine were investigated in four inbred strains of male mice A/J, C57BL/6J, C57BL/6ByJ and BALB/cByJ. Each mouse was injected i.p. once in Experiment 1, or daily for 5 or 11 days in Experiments 2, 3 and 4. Locomotor activity was assessed with an automated photoelectric system. Significant strain differences were found in the response to a single as well as repeated doses of phencyclidine. A/J mice showed the greatest initial response to phencyclidine and developed tolerance to daily phencyclidine. C57BL/6ByJ mice showed initial resistance to acute phencyclidine, but developed sensitization to daily phencyclidine. The responses of both C57BL/6J and BALB/cByJ mice to acute phencyclidine were low to moderate, and did not change significantly following daily phencyclidine. The results of this study indicate that different genetic mechanisms are involved in responses to single and daily injections of phencyclidine.     

Stimulatory effects of ethanol in C57BL/6 mice

Although ethanol stimulation is well documented in several species including humans, there is some controversy about whether the stimulation occurs in the highly inbred mouse strain, C57BL/6. Since inbred mouse strains are frequently used to elucidate mechanisms for individual differences in reaction to alcohol, the present study was undertaken to more completely characterize the behavioral effects of ethanol and to help resolve some of the controversy regarding the drug's stimulatory effect on C57 mice. Activity of female C57BL/6cr mice was assessed in either a lighted or dark environment for 20 min after injections of water or ethanol at doses of 0.5, 1.0, 2.0, 4.0 g/kg. Elevated activity (stimulation) was observed in mice injected with relatively low ethanol doses and tested in the light. The 2.0 g/kg dose produced a transient elevation in activity which declined rapidly across time. Animals tested under the dark condition were not stimulated by the drug but had activity reductions to high doses of ethanol. The detection of ethanol-induced stimulation appears to be related to the performance of control mice rather than a light-related difference in ethanol sensitivity.     

Genotypic variation in the dopaminergic inhibitory control of striatal and hippocampal cholinergic activity in mice

Genotypic variation in dopaminergic-cholinergic interactions in striatum and hippocampus has been investigated in the C57BL/6 and BALB/c mouse strains. Acute treatment in vivo with increasing doses of haloperidol provided behavioural evidence for significant strain-dependent variation in neuroleptic sensitivity as assessed by catalepsy scores with C57BL/6 mice being the more sensitive strain. Measures of the kinetics of high affinity choline uptake in crude synaptosomal preparations of striatum and hippocampus from haloperidol treated mice indicated parallel strain variations for the dose-related activation (dis-inhibition) of cholinergic activity in these regions. The relative involvements of the D1–D2 receptor subpopulations in these effects was investigated using the D2 selective antagonist sulpiride. Sulpiride was also observed to produce similar strain-dependent activation of cholinergic activity in both brain regions whereas behavioural effects were not marked and catalepsy absent in both strains. Comparative in vitro studies on the sensitivity of the dopamine stimulated adenylate cyclase from striatal membranes of both strains failed to reveal significant differences. Genotypic variation in agonist sensitivity was explored using apomorphine. While BALB/c mice exhibited significantly greater sensitivity than C57BL/6 regarding dose effects on stereotypy and rearing, apomorphine was found to be without significant effect in either strain regarding striatal or hippocampal high affinity choline uptake kinetics. These results constitute additional evidence for the proposal that cholinergic activity in striatum and hippocampus is tonically inhibited by dopaminergic mechanisms mediated by the D2 receptor sub-population and further that their density and/or functional activity exhibits significant genotypic variation.     

Mouse strain-dependent hepatic interaction of psychoactive agents with ethanol and biogenic aldehydes metabolizing enzymes

The effect of multiple dose regimens of amantadine, reserpine, chlorpromazine alone or combined on liver alcohol (L-ADH) and aldehyde dehydrogenase (L-ALDH) was studied in three strains of mice. A strain-dependent difference between endogenous specific activity of these enzymes and their sensitivity to the agents studied was determined. The C₅₇BL/6 mice showed most resistance to drug effect and possessed greater activity of mitochondrial L-ALDH isoenzymes and L-ADH than either ICR or BALB/C mouse strains, respectively. Amantadine induced both L-ADH and mitochondrial L-ALDH while reserpine inhibited them also as a function of mouse strain. Both reserpine-and chlorpromazine-mediated inhibition of albino ICR mouse L-ADH and BALB/C mitochondrial L-ALDH was alleviated by pretreatment with amantadine. This indicates antagonism between amantadine and these agents. The results suggest a genotypic sensitivity to drug action which may explain the individual sensitivity to the development of chlorpromazine and reserpine-produced side-effects, and the potency of amantadine in management of such drug-induced adverse reactions.     

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.     

Indomethacin antagonism of ethanol-induced sleep time: Sex and genotypic factors

Pretreatment with prostaglandin synthetase inhibitors (PGSI) significantly decreases the CNS effects of ethanol across the entire ethanol dose-response curve. PGSIs do not significantly affect ethanol metabolism. These effects have been shown in HS/Ibg, LS/Ibg, and SS/Ibg males and females. These strains of mice are useful in alcohol research but are not widely available. The present study examined the possibility of similar effects in C57BL/6 and C3H/2 mice of both sexes. PGSI pretreatment significantly reduced ethanol sleep time across both sexes and genotypes in a dose-dependent manner. Females of both strains required more PGSI to antagonize ethanol's actions relative to males. Within sex, mice with greater sensitivity to ethanol required more PGSI to optimally reduce sleep time than less sensitive mice. These results extend previous findings, and support out hypothesis that one of ethanol's primary mechanisms of action in the CNS is to increase the synthesis of prostaglandins.     

A comparative study of the effect of afobazole on brain monoamine systems in BALB/C and C57BL/6 mice

The comparative study of the effects of afobazole, a novel anxiolytic drug, on the content of brain monoamines and their metabolites in the frontal cortex (FC), hippocampus (HC), hypothalamus (HT), and striatum of BALB/C and C57BL/6 mice (with weak and strong response to emotional stress, respectively) was carried out using HPLC/ED techniques. The norepinephrine (NE) content in the HT of intact C57BL/6 mice is lower, whereas that in the FC and HC of these mice is twice higher than in BALB/C mice. The levels of dopamine (DA) and its metabolites (dioxyphenylacetic and homovanillic acids) in all the brain structures studied was lower in C57BL/6 than in BALB/C mice. Afobazole (1 and 5 mg/kg) increased the NE content in the FC of C57BL/6 mice, while a similar increase in the HC of these mice was observed only upon afobazole injections in a dose of 5 mg/kg. The most prominent changes in the level of DA and its metabolites were observed in the FC, where the DA content significantly decreased after afobazole administration in both doses in BALB/C as well as in C57BL/6 mice. The dose of 1 mg/kg, reduced the DA level in the FC of BALB/C mice more effectively than in animals with active reaction to stress. These results suggest that Afobazole differently modulates the parameters of cathecholaminergic neurotransmission, while not affecting substantially the serotoninergic system in the brain of animals with the different genetically determined stress reaction.     

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     

A diallel analysis of nicotine-induced hypothermia

The hypothermic responses of mice that occur after acute injection of nicotine show genetic influences. The body temperatures of mice of all five strains tested decreased after injection of either 0.75 or 1.5 mg/kg nicotine, but mice of the C3H strain were less affected than were those of the DBA, BALB, or C57BL strains. Mice of the A strain were the most sensitive to nicotine's effects. Genetic effects on nicotine-induced hypothermia were further examined using a five-by-five diallel cross. Additive genetic variance occurred at both nicotine doses. Substantial dominance variance, including directional dominance toward a large hypothermic response induced by injection of a low dose of nicotine (0.75 mg/kg), suggested that an intense response to a low drug dose is adaptive. The directional dominance was absent after treatment with a high dose (1.5 mg/kg) of the drug. Epistatic interactions occurring in crosses involving C57BL mice were pronounced.     

Comparison of neurobehavioral changes in three inbred strains of mice prenatally exposed to methylmercury

Pregnant mice of three inbred strains (BALB/c, C57BL/6J, C57BL/6Cr) were orally given methylmercury (MMC; 3 x 3 mg/kg body weight) or the equivalent volume of phosphate-buffered saline during days 12-14 of gestation and allowed to deliver. The behaviors of their male offspring were evaluated in an open field and their home cage and in a Morris water maze. In the open field test, the BALB/c and C57BL/6Cr MMC groups exhibited less total locomotor activity than did their respective control groups. However, there was no significant difference observed between the MMC and control C57BL/6J strain. In the BALB/c strain, the MMC group exhibited significantly more central locomotion and significantly less peripheral locomotion than did the control group. These results indicated that the prenatal exposure to MMC caused decreases in open-field activity in the C57BL/6Cr and BALB/c strains, concomitantly with a change in emotional status in BALB/c strain. For spontaneous activity in their home cage, all groups moved more actively in the dark phase than in the light phase except BALB/c MMC group. The BALB/c MMC group moved in the light phase as much as in the dark phase, indicating a disturbance of nocturnal rhythm of spontaneous activity. In the Morris water maze, the C57BL/6Cr and C57BL/6J control groups perform very well over the 5 consecutive days. The prenatal exposure to MMC caused significantly prolonged latency in the C57BL/6Cr and C57BL/6J, but not in BALB/c strain. This result indicated that the prenatal exposure to MMC impaired the performance in the Morris water maze differently among the strains. This study provides a basis for evaluating strain-specific neurobehavioral changes when the widely used three inbred strains of mice are chronically exposed to MMC.     

Marked inbred mouse strain difference in the expression of quinpirole induced compulsive like behavior based on behavioral pattern analysis

Obsessive-compulsive disorder (OCD) is a chronic and complex psychiatric disorder with a lifetime prevalence of 2-3%. Recent work has shown that OCD rituals were not only characterized by a high rate of repetition but also by an increased behavioral repertoire due to additional non-functional unique acts. These two behavioral characteristics may provide an ethological basis for studying compulsive behavior in an animal model of OCD. Here, quinpirole induced behavior (so far only investigated in rats) has been studied in A/J and C57BL/6J mice by using behavioral pattern analysis. The aim of this study is to investigate whether genetic background is mediating this behavior. Results showed that open field motor activity levels of saline treated C57BL/6J mice was significantly higher compared to A/J treated saline mice. Long-term quinpirole treatment increased open field motor activity levels in A/J, but not in C57BL/6J. Quinpirole treatment induced a strain dependent difference in behavioral repertoire. There was a dose dependent increase in the number of different behavioral patterns in A/J, whereas, in C57BL/6J there was a dose dependent decrease. This data suggest that genetic background is important in expressing quinpirole induced compulsive like behavior. Following quinpirole treatment, A/J mice express a greater behavioral repertoire with a high rate of repetition. This phenotype resembles that of OCD rituals in patients and indicates that this strain is very interesting to further validate for studying neurobiological mechanisms of compulsive behavior.     

Effects of haloperidol and clozapine on tongue dynamics during licking in CD-1, BALB/c and C57BL/6 mice

Rationale: In an initial effort to describe how genetic background influences the differential motor effects of haloperidol, a drug with high extrapyramidal side effect (EPS) liability, and clozapine, an antipsychotic low in EPS, both drugs were studied in inbred strains of mice (BALB/c and C57BL/6) previously shown to have differential sensitivities to haloperidol. Objectives: Behavioral differences in lick dynamics for male BALB/c, C57BL/6 and CD-1 (an outbred strain) were characterized. Effects of dose ranges of haloperidol and clozapine were then evaluated in the three strains. Methods: The mice learned to lick milk from a force-sensing disk during daily 2-min sessions, while a computer counted the number of licks and measured lick peak force and lick rhythm. After training, acute doses of haloperidol (0.08–2.0 mg/kg) or clozapine (0.5–8.0 mg/kg) were administered i.p. 45 min before sessions. Results: Prior to drug treatment, substantial quantitative strain differences in licking behavior were observed: C57BL/6 mice made fewer licks, licked with lower peak force per lick, and had a slower lick rhythm than the BALB/c and CD-1 mice. As in rats, clozapine slowed the lick rhythm in all three mouse strains much more than haloperidol did. Haloperidol produced a 50% greater suppression of number of licks in BALB/c than in C57BL/6 mice (ED₅₀ values were 0.82 mg/kg and 1.22 mg/kg, respectively). For clozapine, lick suppression was greater in the C57BL/6 than in the BALB/c strain (ED₅₀ values were 1.88 mg/kg and 2.65 mg/kg, respectively). Among the three strains examined, CD-1 was the most sensitive to haloperidol’s suppression of licking, while its sensitivity to clozapine’s lick-suppressing effect was similar to C57BL/6 mice. Clozapine lowered the lick peak force in the CD-1 and BALB/c strains more than in the C57BL/6 strain. Conclusions: Overall, the results suggest that genetic variables may influence both mice’s tongue dynamics and their alteration by both typical and atypical antipsychotic drugs. In addition, while the BALB/c strain was more sensitive to haloperidol’s lick-disruptive effects than the C57BL/6 strain, the size of the difference between strains was much smaller than the reported difference between the strains in the catalepsy test. Received: 19 October 1998 / Final version: 3 June 1999     

Antagonism of the behavioral effects of ethanol by naltrexone in BALB/c,C57BL/6, and DBA/2 mice

The effects of naltrexone on the increase in locomotor activity induced by a low dose (1.35 g/kg IP) of ethanol and on the duration of loss of righting reflex after a high dose (3.5 g/kg) of ethanol were studied in BALB/c, DBA/2, and C57BL/6 mice. Ethanol increased locomotor activity in DBA and BALB mice, but not in C57BL mice. Naltrexone, at a dose of 0.1 mg/kg, antagonized the ethanol-induced increase in locomotion similarly in DBA and BALB mice. The duration of loss of righting reflex was, however, differentially affected in all three strains by naltrexone. The BALB mice affected in all three strains by naltrexone. The BALB mice were the most sensitive strain (1 mg/kg naltrexone significantly counteracted ethanol hypnosis), the C57BL mice were intermediate (8 mg/kg naltrexone required to antagonize this effect of ethanol), and the DBA mice were least sensitive (no effect evident even at the highest dose of 8 mg/kg) to naltrexone. Thus, naltrexone could antagonize the behavioral effects of a low and high dose of ethanol, but the three strains, which differ in their behavioral response to ethanol, also were differentially sensitive to the effect of naltrexone in reversing ethanol-induced hypnosis and ethanol-induced changes in locomotor activity.     

Genetic variation of basal iron status, ferritin and iron regulatory protein in mice: potential for modulation of oxidative stress

Toxic and carcinogenic free radical processes induced by drugs and other chemicals are probably modulated by the participation of available iron. To see whether endogenous iron was genetically variable in normal mice, the common strains C57BL/10ScSn, C57BL/6J, BALB/c, DBA/2, and SWR were examined for major differences in their hepatic non-heme iron contents. Levels in SWR mice were 3- to 5-fold higher than in the two C57BL strains, with intermediate levels in DBA/2 and BALB/c mice. Concentrations in kidney, lung, and especially spleen of SWR mice were also greater than those in C57BL mice. Non-denaturing PAGE of hepatic ferritin from all strains showed a major holoferritin band at approximately 600 kDa, with SWR mice having > 3-fold higher levels than C57BL strains. SDS PAGE showed a band of 22 kDa, mainly representing L-ferritin subunits. A trace of a subunit at 18 kDa was also detected in ferritin from SWR mice. The 18 kDa subunit and a 500 kDa holoferritin from which it originates were observed in all strains after parenteral iron overload, and there was no major variation in ferritin patterns. Although iron uptake studies showed no evidence for differential duodenal absorption between strains to explain the variation in basal iron levels, acquisition of absorbed iron by the liver was significantly higher in SWR mice than C57BL/6J. As with iron and ferritin contents, total iron regulatory protein (IRP-1) binding capacity for mRNA iron responsive element (IRE) and actual IRE/IRP binding in the liver were significantly greater in SWR than C57BL/6J mice. Cytosolic aconitase activity, representing unbound IRP-1, tended to be lower in the former strain. SWR mice were more susceptible than C57BL/10ScSn mice to the toxic action of diquat, which is thought to involve iron catalysis. If extrapolated to humans, the findings could suggest that some people might have the propensity for greater basal hepatic iron stores than others, which might make them more susceptible to iron-catalysed toxicity caused by oxidants.     

Inherent differences in sensitivity to methylxanthines among inbred mice

The behavioral effects of caffeine, theophylline, paraxanthine, and theobromine on locomotor activity were analyzed in four strains of inbred mice that were previously shown to differ in their acute toxic responses to caffeine administered at high dosages. Dose response curves for the effects of caffeine, theophylline, paraxanthine and theobromine on locomotor activity were established in CBA/J, C57BL/6J, DBA/2J and SWR/J strains of inbred mice. Paraxanthine was the maximally effective methylxanthine in the CBA/J, DBA/2J and SWR/J strains, while in the C57BL/6J strain, caffeine was the maximally effective methylxanthine. Theophylline failed to stimulate locomotor activity in the C57BL/6J strain and theobromine failed to stimulate activity in all of the strains tested. Decreases in locomotor activity were seen at the 100 mg/kg dose of caffeine in the C57BL/6J mice and at the 100 mg/kg dose of theophylline in the C57BL/6J, DBA/2J and SWR/J strains. Theobromine produced decreases in locomotor activity in the C57BL/6J, DBA/2J and SWR/J strains of mice. In contrast to the other methylxanthines, paraxanthine failed to decrease activity across the range of doses tested (1.0-150 mg/kg). These data suggest that the methylxanthines have genetically specified multiple modes of action upon locomotor activity and that the use of genetically distinct strains of mice may have important value in the neurochemical and pharmacological dissection of methylxanthine-induced behavioral effects.