Different effects of 3-chlorophenylpiperazine on locomotor activity and acquisition of conditioned avoidance response in different strains of mice

Summary Mice of C57BL/6 (C57), Balb/c (BALB), and CD-1 (CD) strains were injected with 3-chlorophenylpiperazine (CPP), 1–10 mg/kg ip, and their exploratory and basal locomotor activities and acquisition of conditioned avoidance response in a shuttle-box were tested. In C57 mice CPP did not affect either locomotor activity or shuttle-box performance. In BALB mice CPP inhibited both basal and exploratory activities (the latter only in higher doses) and facilitated the acquisition of conditioned avoidance response. In CD mice CPP did not affect exploration, but inhibited basal locomotor activity and facilitated the shuttle-box performance. It is concluded that there exist large interstrain differences in responsiveness of mice to CPP, and that the drug may facilitate acquisition of conditioned avoidance response through a strain-specific, serotonin-independent mechanism.     

The distribution of cocaine in mice differs by age and strain

Few studies have examined the influence of the age and the strain of mouse on the pharmacokinetics of psychostimulants, or the role of pharmacokinetics in age-related differences in drug responses. The present study compared concentrations of cocaine, and its metabolite, benzoylecgonine (BZE), in the blood and brain of early (P35) and later (P42) periadolescent and adult (P63) CD-1 and C57BL/6 male mice 15 min after acute intraperitoneal injection of cocaine (20 mg/kg). Brain levels of cocaine and BZE after seven daily cocaine injections in CD-1 and C57BL/6 mice beginning on P35 and on P63 were also measured. P35 periadolescents of both strains had lower blood cocaine levels than did the adults, but only C57BL/6 periadolescents had lower brain cocaine levels than the adults. C57BL/6 mice of both ages had higher blood cocaine levels than did the corresponding CD-1 mice. Concomitant with lower cocaine levels, periadolescent CD-1 mice had higher blood BZE levels than the adults, suggesting that periadolescents may metabolize cocaine faster. Brain cocaine levels in P42 C57BL/6 mice were similar to those of adults. Cocaine-induced activity did not differ between periadolescent and adult CD-1 mice after a single injection of cocaine, whereas periadolescent C57BL/6 mice had lower activity levels than did the adults after a single cocaine injection. Periadolescent CD-1 mice exhibited higher levels of locomotor activity following cocaine injection than did periadolescent C57BL/6 mice. Following chronic cocaine administration, cocaine and BZE levels in the brains of periadolescent and adult mice did not differ from each other in either strain. However, brain cocaine levels at both ages were lower in CD-1 mice than in C57BL/6 mice. In conclusion, the age and the strain of mouse significantly affect the levels of cocaine obtained in brain and blood following acute administration. Our data are consistent with the notion that CD-1 and C57BL/6 mice metabolize cocaine faster during the early periadolescent period than as adults. Furthermore, potentially important strain differences between CD-1 and C57BL/6 mice were noted in cocaine levels following acute and chronic cocaine administration, and in locomotor activity following acute cocaine administration.     

Indomethacin does not antagonize the anxiolytic action of ethanol in the elevated plus-maze

The present study was designed to examine whether the prostaglandin (PG) synthesis inhibitor indomethacin (INDO) could antagonize the anxiolytic effects of ethanol (EtOH) in the elevated plus-maze test of anxiety. EtOH (1.6 g/kg) significantly increased the percentage of open arm entries and time spent on the open arms in both inbred C57BL/6J and outbred CD-1 mouse strains. However, this anxiolytic effect of EtOH was not significantly antagonized by pretreatment with INDO (5 and 10 mg/kg) in either strain. EtOH also significantly increased total arm entries in CD-1 mice, but not in the C57BL/6J strain. These data from C57BL/6J mice indicate that the low-dose stimulant properties of EtOH can be dissociated from the anxiolytic action of the drug in the plus-maze task. Finally, although INDO did not antagonize the stimulant effect of EtOH in the plus-maze task (in CD-1 mice), it did attenuate EtOH-induced stimulation of locomotor activity in an open-field arena. Taken together, these results suggest some specificity with regard to the role of PGs in mediating (or modulating) the neurobehavioral actions of EtOH, and further support the notion that the anxiolytic and stimulant effects of EtOH may be mediated by different mechanisms.     

Comparison of some biochemical properties of epidermis in tumor promotion-susceptible and -resistant strains of mice

It has been reported that CD-1 and SENCAR mice are susceptible and C57BL/6 mice are resistant to skin tumor promotion caused by phorbol esters. Specific binding of a phorbol ester to its epidermal receptor site, epidermal protein kinase C activity, and ornithine decarboxylase (ODC) induction in epidermis were compared between tumor promotion-susceptible and -resistant strains of mice. Specific binding of [3H]12-O-tetradecanoylphorbol-13-acetate (TPA) to the particulate fraction of the epidermis of C57BL/6 mice gave a similar dissociation constant (Kd) and a maximal number of binding sites (Bmax) to those of CD-1 mice. Protein kinase C activity of the epidermal 105,000 xg supernatant was not significantly different between C57BL/6 and CD-1 mice. Protein kinase C activity of the 105,000 xg pellet, however, was significantly higher in C57BL/6 mice than in CD-1 mice. A topical application of TPA to the skin caused epidermal ODC induction in all of these strains of mice. At any doses of TPA, TPA-induced epidermal ODC activity of C57BL/6 mice was always higher than those of SENCAR and CD-1 mice. Maximal induction of epidermal ODC by TPA was also highest in C57BL/6 mice among these three strains of mice. These results indicate that the mechanism of the difference in susceptibility of C57BL/6, CD-1 and SENCAR mice to the tumor-promoting action TPA resides in a step distal to or other than the protein kinase C activation and ODC induction.     

Locomotor reactivity to a novel environment and sensitivity to MK-801 in five strains of mice

The ability of a noncompetitive antagonist of the N-methyl-D-aspartate receptor, MK-801, to stimulate locomotor activity (LMA) in mice was compared across CD-1, MF1, NIH Swiss (NIHS), C57BL6/J and BALB/C strains with the aim of identifying the most suitable strain for a putative model of schizophrenia. Animals were habituated to novel LMA cages for 1 h before receiving either saline or MK-801 (0.1, 0.32, or 0.5 mg/kg; i.p.) and activity recorded for 2 h. At the end of the test, blood and brain samples were taken and the total concentrations of MK-801 determined. Mice strains differed in habituation; C57BL6/J mice were the most active, whereas BALB/C mice were the least active and slowest to habituate. Robust strain-dependent differences in sensitivity to MK-801 were found, but not to saline. NIHS, C57BL6/J and BALB/C were more active in response to MK-801, exhibiting more rapid, robust and long-lasting increases in LMA than CD-1 or MF1 mice. Total concentrations of MK-801 in the brain did not differ across the strains. We found no correlation between the LMA stimulated by novelty and MK-801. NIHS, C57BL6/J and BALB/C appeared significantly more sensitive to MK-801 than CD-1 and MF1 and can be strains of choice in evaluating the effect of antipsychotic compounds in this model.     

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.     

Locomotion,stereotypy, and dopamine D1 receptors after chronic "binge" cocaine in C57BL/6J and 129/J mice

We have shown that C57BL/6J and 129/J mice differ in their behavioral response to "binge" pattern cocaine (three daily injections of 15 mg/kg separated by 1 h). To determine if these differences persist during chronic binge cocaine administration, we examined the effects of 14-day binge pattern cocaine on home cage behavior. Since the dopamine D(1) receptor may be an important mediator of cocaine-induced locomotor activity, we examined binding to the dopamine D(1) receptor. Locomotor activity was increased by chronic binge cocaine in C57BL/6J (P<.0001) but not in 129/J mice. C57BL/6J mice developed tolerance to the locomotor-activating effects of cocaine. Stereotypic responses were greater in C57BL/6J than in 129/J mice (P=.03), with neither tolerance nor sensitization in either strain. Dopamine D(1) receptor binding in the nucleus accumbens and olfactory tubercle did not differ between strains and was not affected by chronic binge cocaine. In the caudate putamen, subregion specific strain differences in dopamine D(1) receptor binding were observed; chronic binge cocaine increased dopamine D(1) receptor binding in the caudal (P<.05), but not rostral caudate putamen. There was no correlation between locomotor activity or stereotypy and dopamine D(1) receptor density. Thus, with chronic binge cocaine administration, behavioral differences persist between the C57BL/6J and 129/J mice, and cocaine-induced locomotor activity is not correlated with changes in dopamine D(1) receptor binding.     

Effects of acute alcohol administration on object recognition learning in C57BL/6J mice.

The goal of the present study was to investigate effects of alcohol intoxication on the object recognition learning task. Male C57BL/6J mice habituated to saline injections and exploratory arena received different doses of ethanol (0, 1.6 or 2.4 g/kg) before or after a 10-min training session. During training, animals were exposed to a small object (a marble or a die). On the next day, during a 10-min testing session, animals were exposed to two objects: the familiar object from the previous day and a novel object. Analysis of behavior during testing showed that mice injected with 0 and 1.6 g/kg of ethanol before training spent more time exploring a novel than a familiar object during testing. In contrast, mice injected with 2.4 g/kg ethanol spent equal amounts of time exploring the novel and the familiar object. Mice injected with this dose of ethanol after training did not show a decreased ratio of object exploration during testing. Analysis of behavior during training showed that mice injected with this dose of ethanol spent less time exploring the object, although their locomotor activity was not decreased. Our results show that in C57BL/6J mice, ethanol intoxication interferes with exploratory activity during object exploration, but not with consolidation of memory.     

Analysis of the difference in the behavioral effects of apomorphine in C57BL/6 and DBA/2 mice

The influence of pimozide on the effects of apomorphine on locomotor activity and stereotypy was studied in two inbred strains of mice. In C57BL/6 mice, in which apomorphine did not produce stereotypy of gnawing, the biphasic effect of apomorphine on locomotor activity (hypomotility followed by hypermotility) was unaffected by pimozide. In DBA/2 mice, in which high doses of apomorphine produce hypomotility and compulsive gnawing, both these effects (but not hypomotility produced by low doses of apomorphine) were counteracted by pimozide. The results are consistent with the assumption that both strains of mice have separate inhibitory and stimulatory dopamine receptors mediating locomotor activity. In addition, DBA/2 but not C57BL/6 mice have dopamine receptors which mediate stereotypy and are sensitive to pimozide.     

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.     

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.     

An evaluation of the locomotor stimulating action of ethanol in rats and mice

The locomotor activity of groups of three CD-1 female mice was increased by 1.0 and 2.0 g/kg ethanol, IP, was decreased during the first hour and increased during the second hour by 3.0 and 4.0 g/kg, and was decreased by 5.0 g/kg. The dose (2.0 g/kg) that caused the greatest increase in locomotor activity did not impair motor coordination, measured by the height of aerial righting in mice. Tests after oral administration of ethanol showed that the increase in locomotor activity of mice was not due to peritoneal irritation. The same dose (2.0 g/kg) did not increase the locomotor activity of C57BL/6J mice. Ethanol (0.1 to 3.0 g/kg) had no effect or decreased the locomotor activity of individual male Sprague-Dawley rats. These findings suggest that biological differences in strains and species of laboratory rodents contribute to the apparent variability of locomotor stimulation caused by ethanol. The presence or absence of an ethanol-induced increase in locomotor activity was not dependent on the sex or number of mice or rats tested. Intertrial-interval crossing by rats acquiring or performing an active avoidance task in a shuttle box was increased by ethanol. This action was dependent on the presentation of electric foot shock. Apomorphine (0.25 and 2.5 mg/kg) and fenmetozole (7.5 and 15.0 mg/kg) failed to inhibit the ethanolinduced increase in intertrial-interval crossing by rats, although these drugs have been shown previously to antagonize the ethanol-induced increase in the activity of mice ethanol treatment. The ethanol-induced increases in the spontaneous locomotor activity of CD-1 mice in photocell activity monitors and in intertrial-interval crosses in rats in a shuttle box task thus do not appear to share a common mechanism.     

Effects of naloxone on ethanol induced alterations of locomotor activity in C57BL/6 mice

Ethanol (2 g or 3 g/kg) or water vehicle was injected intraperitoneally into C57BL/6 mice 15 min after injections of naloxone, a narcotic analgesic antagonist, or its saline vehicle. Locomotor activity was monitored for 60 min beginning 30 min (Experiment 1) or immediately (Experiment 2) following the ethanol injection. In both experiments, animals injected with the lower dose of ethanol were more active than controls during the second half of the activity test. Animals injected with the high dose of ethanol were less active than controls during the first half of the activity test but returned to control levels or above during the second half of the test. Naloxone at the doses used injected 45 min prior to the activity test (Experiment 1) did not alter locomotor activity and did not influence ethanol induced activity changes. When injected 15 min prior to testing (Experiment 2), however, naloxone alone produced a transient reduction in activity observed only during the first half of testing. During the second half of testing all animals injected with naloxone had activity levels similar to controls and lower than those of animals injected with ethanol in the absence of naloxone. Hence, it appears that naloxone at a dose and time period which does not alter the locomotor activity of mice is capable of blocking ethanol induced excitatory effects.     

Ethanol-induced locomotor stimulation in C57BL/6 mice following RO15-4513 administration

The purpose of this study was to examine the effects of two partial benzodiazepine inverse agonists, RO15-4513 and FG-7142, alone and in combination with ethanol on locomotor activity in C57BL/6 mice. When administered alone, 1.5 g/kg ethanol did not significantly influence activity, confirming previous reports indicating this mouse strain is relatively insensitive to the excitatory properties of ethanol. RO15-4513 treatment also did not significantly influence locomotor activity when administered alone. However, coadministration of RO15-4513 (1.5–6 mg/kg) and ethanol markedly increased locomotor activity. Moreover, the unmasking of ethanol's stimulant action by RO15-4513 (6 mg/kg) was completely reversed by pretreatment with the benzodiazepine receptor antagonist RO15-1788. In contrast, FG-7142 (10–20 mg/kg) increased activity to the same extent in both saline and ethanol-injected mice. This effect was blocked by RO15-1788 pretreatment as well. Neither RO15-4513, FG-7142, nor RO15-1788 significantly influenced blood ethanol concentrations. It is suggested that RO15-4513 unmasked the stimulant effects of ethanol by virtue of its ability to antagonize the depressant properties of ethanol in C57BL/6 mice.     

Behavioral characterization of mice deficient in the phosphodiesterase-10A (PDE10A) enzyme on a C57/Bl6N congenic background

The phenotype of genetically modified animals is strongly influenced by both the genetic background of the animal as well as environmental factors. We have previously reported the behavioral and neurochemical characterization of PDE10A knockout mice maintained on a DBA1LacJ (PDE10A(DBA)) genetic background. The aim of the present studies was to assess the behavioral and neurochemical phenotype of PDE10A knockout mice on an alternative congenic C57BL/6N (PDE10A(C57)) genetic background. Consistent with our previous results, PDE10A(C57) knockout mice showed a decrease in exploratory locomotor activity and a delay in the acquisition of conditioned avoidance responding. Also consistent with previous studies, the elimination of PDE10A did not alter basal levels of striatal cGMP or cAMP or affect behavior in several other well-characterized behavioral assays. PDE10A(C57) knockout mice showed a blunted response to MK-801, although to a lesser degree than previously observed in the PDE10A(DBA) knockout mice, and no differences were observed following a PCP challenge. PDE10A(C57) knockout mice showed a significant change in striatal dopamine turnover, which was accompanied by an enhanced locomotor response to AMPH, These studies demonstrate that while many of the behavioral effects of the PDE10A gene deletion appear to be independent of genetic background, the impact of the deletion on behavior can vary in magnitude. Furthermore, the effects on the dopaminergic system appear to be background-dependent, with significant effects observed only in knockout mice on the C57BL6N genetic background.     

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     

Strain-related differences in bioactivation of vinyl carbamate and formation of DNA adducts in lungs of A/J, CD-1, and C57BL/6 mice.

Inbred strains of mice exhibit differing susceptibilities to formation of lung tumors induced by procarcinogens including ethyl carbamate (EC) and vinyl carbamate (VC). Strain A/J mice are susceptible, whereas C57BL/6 mice are resistant to lung tumor development. In this study, we tested the hypothesis that differential susceptibilities of A/J, CD-1, and C57BL/6 mice to lung tumor development are associated, in part, with their capacities for VC bioactivation and with the extents of DNA adduct formation. Previous studies have shown that the P450 isozyme CYP2E1 and microsomal carboxylesterases are involved in activation and detoxication of VC, respectively. Bioactivation capacity, as estimated by ratios of p-nitrophenol hydroxylase, a CYP2E1 catalytic marker, to carboxylesterase activities, was greater in control A/J (1.32 +/- 0.18 x 10(-6)) and CD-1 (1.25 +/- 0.29 x 10(-6)) mice than in control C57BL/6 (0.69 +/- 0.12 x 10(-6)) mice. The ratios were reduced in all three strains of mice treated with VC. Covalent binding of [(14)C-carbonyl]-VC to lung proteins was time- and dose-dependent, and was significantly higher in A/J and CD-1 mice than in C57BL/6 mice. Experiments using (32)P-postlabeling/thin-layer chromatography showed formation of the DNA adducts 1,N:(6)-ethenodeoxyadenosine and 3,N:(4)-ethenodeoxycytidine in lungs of mice treated with VC. The DNA adducts were detected at 30 min after treatment, peaked at 60 min, and declined thereafter. Levels of 1,N:(6)-ethenodeoxyadenosine and 3,N:(4)-ethenodeoxycytidine were about 70% higher in A/J and CD-1 mice than in C57BL/6 mice. These results indicated that formation of VC metabolites in these murine strains is linked to their bioactivation capacities, and suggested that this attribute may confer differing susceptibilities to lung tumor development.     

Comparison of apomorphine, amphetamine and dizocilpine disruptions of prepulse inhibition in inbred and outbred mice strains

The dopamine agonist apomorphine robustly disrupts prepulse inhibition of the acoustic startle response in the rat, yet published studies have not demonstrated a robust disruption of prepulse inhibition with apomorphine in the mouse. The aim of these studies was to establish the optimal prepulse conditions (using manipulations to prepulse intensity and inter-stimulus interval) and mouse strain(s) for testing apomorphine, and also the prepulse inhibition disrupting drugs amphetamine, and dizocilpine (MK-801). The effects of these drugs on startle response and prepulse inhibition were tested in outbred CD-1 and Swiss Webster (CFW) strains, and the inbred C57BL/6, 129X1/SvJ, and A/J strains. There were strain differences with baseline startle and prepulse inhibition in that the CD-1, CFW, and C57BL/6 strains exhibited high levels of startle and prepulse inhibition, the 129X1/SvJ strain exhibited low levels of startle but high levels of prepulse inhibition, while the A/J strain exhibited low startle and no prepulse inhibition. Apomorphine disrupted prepulse inhibition in the CFW and C57BL/6 strains and the effect was only evident when using a short 30 ms inter-stimulus interval. Amphetamine disrupted prepulse inhibition in the CFW, C57BL/6, and 129X1/SvJ strains, and dizocilpine disrupted prepulse inhibition in the CD-1, CFW, C57BL/6, and 129X1/SvJ strains. The effects of amphetamine and dizocilpine were independent of the inter-stimulus interval. These studies demonstrated clear strain differences in the startle response and prepulse inhibition, and the pharmacological disruptions of prepulse inhibition, and suggest that inter-stimulus intervals less than 100 ms may be optimal for detecting the effects of apomorphine in mice.     

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.     

Haloperiodol-induced microcatalepsy differs in CD-1, BALB/c, and C57BL/6 mice

The degree of arrest of movement (microcatalepsy) induced by haloperidol at doses equipotent for operant rate suppression was measured with computerized instrumentation. The inbred C57BL/6 mouse strain displayed more susceptibility to microcatalepsy than the CD-1 and BALB/c strains. In addition, the C57BL/6 strain exhibited a greater degree of sensitization to repeated dosing than did the other 2 strains. The results were consistent with the C57BL/6 mouse's hypodopaminergic profile reported in the literature but were at odds with results reported for conventional catalepsy testing. The C57BL/6 mouse may serve as a model for genetic vulnerability to extrapyramidal motor side effects and may be useful in quantifying the mild extrapyramidal motor side effects of atypical antipsychotic drugs.