Psychomotor stimulation by dopamine D₁-like but not D₂-like agonists in most mouse strains

Many neurological and psychiatric disorders are treated with dopamine modulators. Studies in mice may reveal genetic factors underlying those disorders or responsiveness to various treatments, and species and strain differences both complicate the use of mice and provide valuable tools. We evaluated psychomotor effects of the dopamine D?-like agonist R-6-Br-APB and the dopamine D?-like agonist quinelorane using a locomotor activity procedure in 15 mouse strains (inbred 129S1/SvImJ, 129S6/SvEvTac, 129X1/SvJ, A/J, BALB/cByJ, BALB/cJ, C3H/HeJ, C57BL/6J, CAST/EiJ, DBA/2J, FVB/NJ, SJL/J, SPRET/EiJ, outbred Swiss Webster, and CD-1) and Sprague-Dawley rats, using groups of both females and males. Both D? and D? stimulation produced hyperactivity in the rats, and surprisingly, only two mouse strains were similar in that regard (C3H/HeJ, SPRET/EiJ). In contrast, the majority of mouse strains exhibited hyperactivity only with D? stimulation, whereas D? stimulation had no effect or decreased activity. BALB substrains, A/J and FVB/NJ mice showed only decreased activity after either D? or D? stimulation. CAST/EiJ mice exhibited hyperactivity exclusively with D? stimulation. Sex differences were observed but no systematic trend emerged: For example, of the five strains in which a main factor of sex was identified for the stimulant effects of the D? agonist, responsiveness was greatest in females in three of those strains and in males in two of those strains. These results should aid in the selection of mouse strains for future studies in which D? or D? responsiveness is a necessary consideration in the experimental design.     

Mitochondrial bioenergetics and drug-induced toxicity in a panel of mouse embryonic fibroblasts with mitochondrial DNA single nucleotide polymorphisms

Mitochondrial DNA (mtDNA) variations including single nucleotide polymorphisms (SNPs) have been proposed to be involved in idiosyncratic drug reactions. However, current in vitro and in vivo models lack the genetic diversity seen in the human population. Our hypothesis is that different cell strains with distinct mtDNA SNPs may have different mitochondrial bioenergetic profiles and may therefore vary in their response to drug-induced toxicity. Therefore, we used an in vitro system composed of four strains of mouse embryonic fibroblasts (MEFs) with mtDNA polymorphisms. We sequenced mtDNA from embryonic fibroblasts isolated from four mouse strains, C57BL/6J, MOLF/EiJ, CZECHII/EiJ and PERA/EiJ, with the latter two being sequenced for the first time. The bioenergetic profile of the four strains of MEFs was investigated at both passages 3 and 10. Our results showed that there were clear differences among the four strains of MEFs at both passages, with CZECHII/EiJ having a lower mitochondrial robustness when compared to C57BL/6J, followed by MOLF/EiJ and PERA/EiJ. Seven drugs known to impair mitochondrial function were tested for their effect on the ATP content of the four strains of MEFs in both glucose- and galactose-containing media. Our results showed that there were strain-dependent differences in the response to some of the drugs. We propose that this model is a useful starting point to study compounds that may cause mitochondrial off-target toxicity in early stages of drug development, thus decreasing the number of experimental animals used.     

Psychomotor stimulant effects of cocaine in rats and 15 mouse strains

Relative to intravenous drug self-administration, locomotor activity is easier to measure with high throughput, particularly in mice. Therefore its potential to predict differences in self-administration between genotypes (e.g., targeted mutations, recombinant inbred strains) is appealing, but such predictive value is unverified. The main goal of this study was to evaluate the utility of the locomotor assay for accurately predicting differences in cocaine self-administration. A second goal was to evaluate any correlation between activity in a novel environment, and cocaine-induced hyperactivity, between strains. We evaluated locomotor activity in male and female Sprague-Dawley rats and 15 mouse strains (129S1/SvImJ, 129S6/SvEvTac, 129X1/SvJ, A/J, BALB/cByJ, BALB/cJ, C3H/HeJ, C57BL/6J, CAST/EiJ, DBA/2J, FVB/NJ, SJL/J, SPRET/EiJ, and outbred Swiss Webster and CD-1/ICR), as well as cocaine self-administration in BALB substrains. All but BALB/cJ mice showed locomotor habituation and significant cocaine-induced hyperactivity. BALB/cJ mice also failed to self-administer cocaine. BALB/cByJ mice showed modest locomotor habituation, cocaine-induced locomotion, and cocaine self-administration. As previously reported, female rats showed greater cocaine-induced locomotion than males, but this was only observed in one of 15 mouse strains (FVB/NJ), and the reverse was observed in two strains (129X1/SvJ, BALB/cByJ). The intriguing phenotype of the BALB/cJ strain may indicate some correlation between all-or-none locomotion in a novel environment, and stimulant and reinforcing effects of cocaine. However, neither novelty- nor cocaine-induced activity offered a clear prediction of relative reinforcing effects among strains. Additionally, these results should aid in selecting mouse strains for future studies in which relative locomotor responsiveness to psychostimulants is a necessary consideration.     

Plasma microRNAs are sensitive indicators of inter-strain differences in the severity of liver injury induced in mice by a choline- and folate-deficient diet

MicroRNAs (miRNAs) are a class of small, conserved, tissue-specific regulatory non-coding RNAs that modulate a variety of biological processes and play a fundamental role in the pathogenesis of major human diseases, including nonalcoholic fatty liver disease (NAFLD). However, the association between inter-individual differences in susceptibility to NAFLD and altered miRNA expression is largely unknown. In view of this, the goals of the present study were (i) to determine whether or not individual differences in the extent of NAFLD-induced liver injury are associated with altered miRNA expression, and (ii) assess if circulating blood miRNAs may be used as potential biomarkers for the noninvasive evaluation of the severity of NAFLD. A panel of seven genetically diverse strains of inbred male mice (A/J, C57BL/6J, C3H/HeJ, 129S/SvImJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ) were fed a choline- and folate-deficient (CFD) diet for 12 weeks. This diet induced liver injury in all mouse strains; however, the extent of NAFLD-associated pathomorphological changes in the livers was strain-specific, with A/J, C57BL/6J, and C3H/HeJ mice being the least sensitive and WSB/EiJ mice being the most sensitive. The morphological changes in the livers were accompanied by differences in the levels of hepatic and plasma miRNAs. The levels of circulating miR-34a, miR-122, miR-181a, miR-192, and miR-200b miRNAs were significantly correlated with a severity of NAFLD-specific liver pathomorphological features, with the strongest correlation occurring with miR-34a. These observations suggest that the plasma levels of miRNAs may be used as biomarkers for noninvasive monitoring the extent of NAFLD-associated liver injury and susceptibility to NAFLD.     

Antidepressant response to chronic citalopram treatment in eight inbred mouse strains

Rationale

The antidepressant response exhibits a characteristic delay. BALB/cJ mice respond to chronic, but not subchronic, treatment with selective serotonin reuptake inhibitors (SSRIs), providing a model of antidepressant onset. Identification of other mouse strains exhibiting this phenotype will provide additional tools for studying mechanisms of the antidepressant response.

Objectives

We aimed to identify inbred mouse strains that respond to chronic, but not subchronic, SSRI treatment in the forced swim test (FST). We also assessed whether response correlated with genotype at the functional C1473G polymorphism in tryptophan hydroxylase-2 (Tph2).

Methods

BALB/cJ, three closely related strains (BALB/cByJ, SEA/GnJ, A/J), and four distantly related strains (C57BL/6J, C57BL/10J, CAST/EiJ, SM/J) received the SSRI citalopram (0?C30?mg/kg/day in drinking water) for ~4?weeks and were assessed for locomotion and FST behavior. Citalopram-responsive strains were assessed identically following ~1?week of treatment. C1473G genotypes were determined.

Results

BALB/cJ and related strains carried the 1473G allele and responded to chronic citalopram treatment in the FST. BALB/cJ, BALB/cByJ, and SEA/GnJ mice showed either no response or an attenuated response to subchronic treatment. Distantly related strains carried the 1473C allele and showed no response to citalopram. No relationship was found between the antidepressant response and baseline immobility or locomotion.

Conclusions

BALB/cJ and related strains exhibit an antidepressant response to chronic SSRI treatment that emerges over time and is likely a heritable trait. This antidepressant response is associated with carrying the 1473G allele in Tph2. In conclusion, BALB/cJ and related strains provide valuable models for studying the therapeutic mechanisms of SSRIs.     

Reexamination of the relationship between alcohol preference and brain monoamines in inbred strains of mice including senescence-accelerated mice

The relationship between voluntary alcohol consumption and brain monoamine levels was studied in the inbred strains of C57BL/6N, C57BL/6J, A/J, BALB/cA, CBA/N, C3H/He and DBA/2cr mice; the congeneric mouse strain, B10.Br/Sg, and the senescence accelerated mouse (SAM P1, SAM P2). The C57BL strains exhibited a high alcohol preference whereas the other strains exhibited a low alcohol preference. A clear positive relationship was found between alcohol intake (g/kg/day) and brain norepinephrine level (r = 0.683, p less than 0.05), and a clear negative relationship between alcohol intake and brain serotonin level (r = -0.628, p less than 0.05). The content of brain dopamine was not clearly correlated with alcohol intake (r = -0.206, p greater than 0.05). These findings suggest that in mice voluntary alcohol preference is influenced by brain norepinephrine and serotonin levels genetically.     

人常见白血病小鼠模型及其应用

人常见白血病小鼠模型除C57BL、L615和BALB／c等近交系小鼠,还有BALB／c—nu／nu、SCID、NOD／SCID、NOD／SCID／Bmull和NOD／SCID／ycmull等突变系小鼠,本文综述近年上述两大类小鼠的白血病模型建立及其应用评价。     

Strain-dependent antidepressant-like effects of citalopram in the mouse tail suspension test

Rationale Variations in the effects of antidepressant drugs between different mouse strains are important for drug discovery and could lead to the identification of genes that predict differences in drug efficacy.Objectives This study compared behavioral baselines and dose-dependent responses to the selective serotonin reuptake inhibitor (SSRI) citalopram in eight inbred mouse strains (C57BL/6J, DBA/2J, C3H/HeJ, BALB/cJ, A/J, 129/SvEmsJ, 129/SvImJ, and BTBR) using the tail suspension test (TST).Results The DBA/2J, BALB/cJ, and BTBR strains were the most responsive to the effects of citalopram. Citalopram was least effective in the C57BL/6J and A/J strains. The antidepressant-like effects of citalopram in the TST were not correlated with changes in locomotor activity or deprivation-induced feeding behavior across the individual mouse strains, suggesting that patterns of sensitivity to citalopram are behaviorally specific and unlikely to result from pharmacokinetic variables. As an initial search for genetic polymorphisms causing differences in citalopram sensitivity, polymorphic forms of the tryptophan hydroxylase 2 (tph2) gene were genotyped and found to be not correlated with citalopram responsive (DBA/2J and BALB/cJ) and nonresponsive (A/J and C57BL/6J) strains.Conclusions The TST strain survey described here: (1) suggested the most appropriate strains for screening potential antidepressants, (2) identified parental strains appropriate for quantitative trait loci mapping of genomic loci regulating SSRI sensitivity, and (3) indicated appropriate background strains for measuring an antidepressant-like response to the SSRI citalopram. The pattern of response agrees with a previous mouse strain survey that examined sensitivity to fluoxetine in the forced swim test (Lucki I, Dalvi A, Mayorga AJ (2001) Sensitivity to the effects of pharmacologically selective antidepressants in different strains of mice. Psychopharmacology 155:315–322).     

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.     

C57BL/6J mice show greater amphetamine-induced locomotor activation and dopamine efflux in the striatum than 129S2/SvHsd mice

Inbred strains of mice have served as valuable models for studying genetic susceptibility to drug addiction, an alternative to genetically modified mouse models. This is the first study comparing amphetamine (AMPH) effects on locomotor stimulation and dopamine efflux between two inbred strains of mice C57BL/6J and 129S2/SvHsd, frequently used as background strains for production of genetically engineered mice. There were no significant differences in basal locomotor activity and basal dopamine levels between the two strains. However, C57BL/6J mice showed greater AMPH-stimulated locomotor activity and AMPH-induced striatal dopamine efflux than 129S2/SvHsd mice. The differential AMPH effects could not be explained by differences in presynaptic dopamine components such as surface and total dopamine transporter (DAT) expression levels, striatal dopamine contents, and DAT activity. C57BL/6J and 129S2/SvHsd mice are excellent models for future identification of genetic, molecular, and behavioral components related to individual vulnerability to AMPH addiction. This study emphasizes the importance of mouse strain selections in the production of genetically modified mice for investigating phenotypes and mechanisms of psychostimulants.     

Strain differences in haematological response to chloramphenicol succinate in mice: implications for toxicological research.

Much toxicological research continues to be done using genetically undefined "outbred" stocks of mice and rats, although the case for using isogenic strains has been made repeatedly in the literature over a period of more than two decades. Also, very few studies are conducted using more than one strain, with the result that genetic variation in response is seldom apparent to the investigator. Here we report qualitative and quantitative strain differences in the haematological response to chloramphenicol succinate (CAPS) when administered by gavage at 500-2500 mg/kg for 7 days, to four inbred strains of mouse (C3H/He, CBA/Ca, BALB/c and C57BL/6) and one outbred stock (CD-1). CAPS caused anaemia and reticulocytopenia in all mouse strains, and leucopenia in the inbred strains but not in the outbred CD-1 stock. All four inbred strains showed significant (P<0.01) responses to CAPS at lower dose levels than in CD-1 mice, which were phenotypically more variable than the inbred animals. A simulated experiment, using a sample of records from the present study, showed that the use of two mice at each dose level using CD-1, CBA, BALB/c and C57BL/6 (48 total mice), would have given a more sensitive experiment than the use of 47 CD-1 mice alone, and would also have shown that the response is partly strain dependent. These studies provide additional evidence that inbred strains, because of their greater sensitivity and other valuable properties, should be more widely used in toxicology.     

Modulation of mouse brain dopamine,serotonin and metabolites by methionine: Implications for schizophrenia and genetics

The effect of methionine, an essential amino acid, on brain regional distribution of dopamine, serotinin and major acidic metabolites was studied in two genetically different strains of mice. These were the inbred albino BALB/C and the black C₅₇BL/6 mouse strains. The later strain was more sensitive than the former mouse strain to the methionine treatment. This has been demonstrated by methionine-produced change in dopamine metabolites in cerebellum, cortex and medulla regions, which suggests a decrease in dopamine turnover in the C₅₇BL/6 mice. Conversely, methionine-mediated changes in BALB/C mouse medullary region was suggestive of an increase in dopamine turnover. Little changes occurred in cerebral serotonin or 5-hydroxyindoleacetic acid levels, except for an increased serotonin in C₅₇BL/6 mouse midbrain region. The results suggest that methionine possesses CNS pharmacological property pertaining to dopamine, other than its well-known action as a methyl donor in transmethylation processes, which is genotypic-dependent. Alternatively, modulation of the monoamines by methionine may explain its antidepressant property and possible contribution to the pharmacological hypotheses relevant to the biology of schizophrenia.     

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.     

Genetic control of acetyl coenzyme A-dependent arylamine N-acetyltransferase, hydrazine N-acetyltransferase, and N-hydroxy-arylamine O-acetyltransferase enzymes in C57BL/6J, A/J, AC57F1, and the rapid and slow acetylator A.B6 and B6.A congenic inbred mouse

Acetyl coenzyme A-dependent N-acetyltransferase and O-acetyltransferase activities were examined in liver cytosols derived from homozygous rapid acetylator C57BL/6J and A.B6 congenic inbred mouse strains, from homozygous slow acetylator A/J and B6.A congenic inbred mouse strains, and from the (C57BL/6J x A/J)F1 heterozygous acetylator hybrid mouse strain. Acetylator genotype-dependent N-acetyltransferase activity was exhibited for the N-acetylation of p-aminobenzoic acid, 2-aminofluorene, and 4-aminobiphenyl. In contrast, levels of isoniazid N-acetyltransferase and N-hydroxy-3,2'-dimethyl-4-aminobiphenyl O-acetyltransferase activities in mouse liver cytosol appeared to be independent of the arylamine Nat acetylator gene. Although cytosolic N-acetyltransferase activities differed about 2-fold between the parental C57BL/6J and A/J strains for p-aminobenzoic acid, 2-aminofluorene, and 4-aminobiphenyl, the same N-acetyltransferase activities differed about 6-7-fold between the homozygous rapid acetylator A.B6 and the homozygous slow acetylator B6.A congenic inbred strains. Partial purification of acetyl coenzyme A-dependent arylamine N-acetyltransferase activity in the five inbred mouse strains showed one major paraoxon-resistant enzyme in liver cytosol in each of the rapid and slow acetylator mouse strains examined. Levels of partially purified 2-aminofluorene and 4-aminobiphenyl N-acetyltransferase activity were about 7-fold higher in the A.B6 than the B6.A congenic inbred strain. Partial purification of acetyl coenzyme A-dependent isoniazid N-acetyltransferase activity showed catalysis by a paraoxon-resistant enzyme(s) distinct from the major arylamine N-acetyltransferase enzyme(s). These results suggest that isoniazid N-acetyltransferase(s) in mouse liver cytosol is a product of a separate gene that segregates independently of the arylamine Nat gene.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Dissimilar effects of subchronic clozapine and haloperidol on operant lever pressing in C57BL/6J, BALB/cJ, and LP/J mice

The effects of the atypical antipsychotic, clozapine, and the typical antipsychotic, haloperidol, on operant behavior have been well described in the rat; however, little such work has been done with mice. In the present study, the effects of clozapine (2.0, 4.0, and 6.0 mg/kg) and haloperidol (0.06, 0.13, and 0.25 mg/kg) were evaluated in three inbred strains of mice (C57BL/6J, BALB/cJ, and LP/J mice) across six consecutive daily sessions at each dose, in which each lever press produced access to milk. Tolerance to the rate-reducing effects of clozapine was observed in the BALB/cJ strain, but not in the C57BL/6J and LP/J strains. In contrast, sensitization was observed in the three mouse strains treated with subchronic haloperidol. These results are at odds with the operant rat literature on the effects of clozapine, but are consistent with the idea that genetic variables contribute, at least in part, to some of the differences observed in response to antipsychotics.     

Inbred strain differences in prepulse inhibition of the mouse startle response

 Prepulse inhibition is the phenomenon in which a weak prepulse stimulus suppresses the response to a startling stimulus. Patients with schizophrenia have impaired prepulse inhibition which is thought to reflect dysfunctional sensorimotor gating mechanisms. To investigate the potential genetic basis for differences in sensorimotor gating, the responses of 13 inbred strains of mice were evaluated using the prepulse inhibition paradigm. Ten male mice from A/J, AKR/J, BALB/cByJ, BUB/BnJ, C3H/HeJ, C57BL/6J, C57BL/10J, DBA/2J, FVB/NJ, ST/bJ, 129/J, 129/SvJ, 129/SvEvTac inbred strains were tested for acoustic prepulse inhibition of acoustic and tactile startle responses. There was a wide range of responses among the inbred strains of mice. Exact strain distributions were determined for each combination of prepulse sound level and startle stimulus. In general, mice from the 129/SvEvTac, AKR/J, 129/J, and 129/SvJ strains displayed high levels of prepulse inhibition of both the acoustic and tactile startle responses. C57BL/6J, C57BL/10J and BUB/BnJ mice showed low levels of prepulse inhibition. There was also a wide range in the amplitude of the acoustic and tactile startle responses. C57BL/10J and FVB/NJ mice displayed the greatest startle responses and DBA/2J, 129/J and 129/SvJ had the poorest startle responses. There was no correlation between the level of prepulse inhibition and the amplitude of the startle response. These findings indicate that inbred strains of mice may be a useful tool to study the genetic basis of sensorimotor gating. Received:8 October 1996 / Final version: 10 December 1996     

The effects of cocaine on operant responding for food in several strains of mice

 The availability of numerous genetically homogenous mouse strains permits the analysis of genetic influences on behavior and also behavioral sensitivity (responsivity) to drugs of abuse. The current study was conducted to characterize discriminated operant responding for food in four inbred strains (Balb/cByJ, DBA/2J, C57BL/6J, SJL/J), an F1 Hybrid (C57BL/6×SJL), and one outbred strain (CD1) of mouse. The effect of cocaine on this operant behavior was also examined. Initially, all animals were trained to nosepoke for food on a continuous reinforcement schedule. The minimum response requirement for reinforcement was increased every 5 days until the animals were responding on an FR-15 schedule of reinforcement. All strains increased operant responding as the schedule of reinforcement was raised. However, significant differences in response rate and discrimination learning were observed among the various strains of mice. Cocaine administration reduced operant responding for food in Balb/cByJ, C57BL/6J, C57BL/6×SJL/J and CD1 mice at a dose of 15.0 mg/kg, whereas higher doses were required in DBA/2J mice (30.0 mg/kg) and SJL/J mice (56.0 mg/kg). These results suggest that operant performance and the effect of cocaine on this behavior is differentially influenced by genetic make-up. Received: 20 December 1996 / Final version: 4 April 1997