Genotypic influences on striatal dopaminergic regulation in mice

Genotypic influences on dopaminergic-induced behaviors and striatal dopaminergic receptors were evaluated in CBA/J, C57BL/6J and BALB/cJ male mice. CBA/J mice were less behaviorally sensitive to apomorphine (stereotypic behavior), but more sensitive to haloperidol (catalepsy) than C57BL/6J and BALB/cJ mice. Striatal dopaminergic receptors, assayed by binding of [³H]spiroperidol (antagonist) and [³H]ADTN (agonist), were 50% fewer in CBA/J compared to BALB/cJ mice; C57BL/6J mice had low to intermediate numbers of receptors.

Striatal dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations were similar in all strains. However, a 20% higher DOPAC/dopamine ratio in CBA/J mice suggests greater dopamine turnover. Median eminence dopamine was similar in all strains, but norepinephrine was 30% higher in BALB/cJ mice.

CBA/J mice failed to show antagonist-induced supersensitivity-type responses to chronic haloperidol treatment: enhanced stereotypic response to apomorphine and a 30% increase of dopaminergic receptors occurred in C57BL/6J and BALB/cJ mice, but not in CBA/J mice. These data suggest that CBA/J mice either cannot respond to chronic haloperidol treatment or have an elevated threshold for induction of supersensitivity response.

Chronic treatment with the dopamine agonist bromocriptine (7d) depressed apomorphine-induced stereotypic behavior in C57BL/6J mice and eliminated stereotypy in BALB/cJ mice, but caused no change in stereotypic behavior in CBA/J mice. Dopaminergic receptors were 15% lower after bromocriptine treatment in all strains.

These results suggest that some striatal dopaminergic functions are impaired in CBA/J mice relative to BALB/cJ and C57BL/6J mice. The impaired haloperidol-induced supersensitivity responses in the CBA/J mouse may be a useful model for analyzing similar impairments of supersensitivity responses in old rodents.     

Genotypic influences on pituitary responsiveness to haloperidol in mice

Previous studies from this laboratory demonstrated that CBA/J mice have impaired striatal dopaminergic supersensitivity in response to subchronic haloperidol administration. Others have speculated that the peripheral hyperprolactinemia produced by haloperidol is necessary for the striatal dopamine receptor supersensitization produced by dopamine antagonists. In the present experiments, we tested the hypothesis that the impaired supersensitization response to haloperidol in CBA/J mice was secondary to an impaired hyperprolactinemic response by comparing the CBA/J mice with other mice that show normal supersensitization responses: the BALB/cJ and C57BL/6J strains. Acute haloperidol treatments increased serum prolactin levels 60 min later in all three strains, with the greatest response in CBA/J mice. After longer haloperidol treatment (2 or 21 days), serum prolactin remained elevated in CBA/J and, to a lesser extent, in C57BL/6J mice; levels remained low throughout treatment in BALB/cJ mice. Although, the basal density of pituitary dopamine receptors [( 3H]spiperone or D-2 binding sites) was greater in CBA/J than BALB/cJ mice, only BALB/cJ mice showed increased pituitary D-2 binding sites following chronic haloperidol administration. Taken together with previous studies of dopamine and noradrenaline receptors in these mouse strains, we conclude that CBA/J mice have a generalized impairment in their supersensitization responses to pharmacologic blockade of receptors. These data do not support the involvement of prolactin in haloperidol-induced dopamine receptor up-regulation.     

Dopamine synthesis in inbred mouse strains which differ in numbers of dopamine neurons

BALB/cJ and CBA/J mice have been shown to have different numbers of dopamine (DA) neurons in the central nervous system, with BALB/cJ mice having 20–50% more DA neurons in each dopaminergic cell group which is reflected in a difference in tyrosine hydroxylase activity in these cell groups. The present study compared the levels of DA and the rate of DA synthesis between these two inbred mouse strains. Three measures were used to reflect the rate of DA synthesis: the levels of DA metabolites (DOPAC and HVA) in the striatum, the rate of disappearance of DA following inhibition of tyrosine hydroxylase withα-methyl-P-tyrosine, and the rate of accumulation of DOPA following inhibition of aromatic amino acid decar☐ylase with NSD-1015. Striatal DA levels were slightly higher in CBA/J mice than BALB/cJ mice. The rate of DA synthesis in the striatum, as estimated from the accumulation of DOPA following NSD-1015 injection or from the decline of DA levels followingα-methyl-p-tyrosineinjection, was from 30–50% greater in the BALB/cJ mice compared to the CBA/J mice. In striatum, DOPAC levels were higher, HVA levels lower, and DOPAC plus HVA levels equal in CBA/J mice compared to BALB/cJ mice. The results show that BALB/cJ mice, with more DA neurons than CBA mice, also synthesize more DA. In addition, the data suggest that DA levels do not necessarily reflect numbers of DA neurons, and that catecholamine metabolite levels are not a good measure for comparing catecholamine synthesis between inbred animal strains.     

Genetic variations in midbrain dopamine cell number: Parallel with differences in responses to dopaminergic agonists and in naturalistic behaviors mediated by central dopaminergic systems

Mice of the inbred strain BALB/cJ have more midbrain dopaminergic cell bodies and greater activity of the catecholamine-synthesizing enzyme, tyrosine hydroxylase (TH), in the nigrostriatal and mesolimbic dopaminergic systems than mice of the CBA/J strain. This difference in cell number and TH activity in the midbrain dopaminergic systems are paralleled by differences in drug responses and behaviors which are dependent on the release of dopamine in midbrain dopaminergic system. BALB/cJ mice showed greater locomotion and stereotypy than CBA/J mice after D-amphetamine (2-20 mg/kg, i.p.). There was no difference in the amount of amphetamine accumulated in brain at the peak of drug response or in the duration of drug effect, suggesting that the differences in behavioral effect were not due to strain differences in pharmacokinetic distribution of the drug. In contrast to the greater stereotypy to D-amphetamine, BALB/cJ mice showed less stereotypy after apomorphine (2-10 mg/kg, i.p.) than CBA/J mice. BALB/cJ mice also showed more exploration than CBA/J mice, measured as locomotion and rearing in a novel open field and investigation of a novel object. Genetically determined differences in the number of midbrain dopaminergic cell bodies and in the relative density of innervation of DA terminals in target fields and in TH activity in the nigrostriatal and mesolimbic dopaminergic systems are paralleled by difference in behavioral responses mediated by release of dopamine. The number of cells of a particular neurochemical class may dictate the magnitude of behaviors, drug-induced or spontaneous, mediated by those neurons.     

Strain differences in pituitary prolactin content: Relationship to number of hypothalamic dopamine neurons

BALB/cJ mice have more tuberoinfundibular dopamine neurons, and thus greater tyrosine hydroxylase activity, than CBA/J mice. Strain differences in the synthesis and release of prolactin would also be predicted since dopamine released from the tuberoinfundibular neurons is the prolactin inhibitory factor which plays a role in the regulation of both prolactin synthesis and release. As expected, CBA/J mice, with fewer dopamine neurons, synthesized and released significantly more prolactin than BALB/cJ mice; that is, both pituitary and serum prolactin concentrations were greater in CBA/J mice. To determine if there were more cells containing prolactin or more prolactin per cell, pituitaries were stained with antibodies to prolactin and densitometric analysis made of both the average staining per unit area and total staining per pituitary. For both indices CBA/J mice had more staining than BALB/cJ mice. Using these criteria the difference in staining was attributed to more prolactin-stained lactotrophs in the CBA/J strain. Although no differences in the number of acidophils demonstrated by Pearse Trichrome method were observed, acidophils from BALB/cJ mice appeared smaller and contained less cytoplasm than those from CBA/J mice. We conclude that strain differences in the number of tuberoinfundibular dopamine neurons are inversely related to the number of immunocytochemically demonstrable prolactin-containing cells in the anterior pituitary.     

Genetic variance contributes to naltrexone-induced inhibition of sucrose intake in inbred and outbred mouse strains

The study of genetic variance in opioid receptor antagonism of sucrose and other forms of sweet intake has been limited to reductions in sweet intake in mice that are opioid receptor-deficient or lacking either pre-pro-enkephalin or beta-endorphin. Marked genetic variance in inbred mouse strains has been observed for sucrose intake across a wide array of concentrations in terms of sensitivity, magnitude, percentages of kilocalories consumed as sucrose and compensatory chow intake. The present study examined potential genetic variance in systemic naltrexone's dose-dependent (0.01-5 mg/kg) and time-dependent (5-120 min) ability to decrease sucrose (10%) intake in eleven inbred (A/J, AKR/J, BALB/cJ, CBA/J, C3H/HeJ, C57BL/6J, C57BL/10J, DBA/2J, SJL/J, SWR/J, 129P3/J) and one outbred (CD-1) mouse strains. A minimum criterion sucrose intake (1 ml) under vehicle treatment, designed to avoid "floor effects" of antagonist treatment was not achieved in three (A/J, AKR/J, CBA/J) inbred mouse strains. Marked genetic variance in naltrexone's ability to inhibit sucrose intake was observed in the remaining strains with the greatest sensitivity observed in the C57BL/10J and C57BL/6J strains, intermediate sensitivity in BALB/cJ, C3H/HeJ, CD-1 and DBA/2J mice, and the least sensitivity in 129P3/J, SWR/J and SJL/J strains with a 7.5-36.5 fold range of greater effects in the ID(50) of naltrexone-induced inhibition in C57BL/10J relative to the three less-sensitive strains across the time course. Naltrexone primarily affected the maintenance, rather than the initiation of intake in BALB/cJ, CD-1, C3H/HeJ, DBA/2J and SJL/J mice, but significantly reduced sucrose intake at higher doses across the time course in C57BL/6J, C57BL/10J and 129P3/J mice. Whereas SWR/J mice failed to display any significant reduction in sucrose intake at any time point following any of the naltrexone doses, naltrexone's maximal magnitude of inhibitory effects was small (35-40%) in 129P3/J and SJL/J mice, moderate ( approximately 50%) in BALB/cJ, C3H/HeJ, CD-1 and DBA2/J mice, and profound (70-80%) in C57BL/6J and C57BL/10J mice. Indeed, the latter two strains displayed significantly greater percentages of naltrexone-induced inhibition of sucrose intake than virtually all other strains. These data indicate the importance of genetic variability in opioid modulation of sucrose intake.     

Sexual differences and estrous cycle in methamphetamine-induced dopamine and serotonin depletions in the striatum of mice

Summary. Four consecutive doses (10 mg/kg) of methamphetamine, s.c., produced a substantial striatal dopamine depletion in both sexes of BALB/c and C57BL/6J mice. Male C57BL/6J mice exhibited greater dopamine depletions in the striatum compared to female C57BL/6J mice. In contrast, male and female BALB/c mice demonstrated an equivalent magnitude of striatal dopamine depletion. Regardless of sex, C57BL/6J mice demonstrated approximately 1.4 to 2.2 times greater dopamine depletions in the striatum compared to BALB/c mice. Moreover, methamphetamine caused 4 times greater serotonin depletions in male as opposed to female BALB/c mice while sparing either sex of the C57BL/6J mice. Furthermore, female mice of both strains appeared to have the greatest basal dopamine levels during proestrus and the lowest basal dopamine levels during diestrus. Likewise, female mice of both strains exhibited the lowest dopamine depletions in the striatum when the dosing regimen of methamphetamine started at proestrus whereas the greatest dopamine depletions in the striatum occurred when the regimen started during diestrus. These results suggest that sex hormones and other modulating factors may play a role in methamphetamine-induced dopamine and serotonin neurotoxicity. Received August 3, 1999; accepted September 13, 1999     

Variations in number of dopamine neurons and tyrosine hydroxylase activity in hypothalamus of two mouse strains

Mice of the BALB/cJ strain have more neurons and greater tyrosine hydroxylase (TH) activity in the midbrain than mice of the CBA/J strain (Baker, H., T. H. Joh, and D. J. Reis (1980) Proc. Natl. Acad. Sci. U.S.A. 77: 4369-4373). To determine whether the strain differences in dopamine (DA) neuron number and regional TH activity are more generalized, regional TH activity was measured and counts of neurons containing the enzyme were made in the hypothalamus of male mice of the BALB/cJ and CBA/J strains. TH activity was measured in dissections of whole hypothalamus (excluding the preoptic area), the preoptic area containing a rostral extension of the A14 group, the mediobasal hypothalamus containing the A12 group, and the mediodorsal hypothalamus containing neurons of the A13 and A14 groups. Serial sections were taken and the number of DA neurons was established by counting at 50- to 60-microns intervals all cells stained for TH through each area. In conjunction with data obtained biochemically, the average amount of TH per neuron was determined. In all areas, TH activity in CBA/J mice was significantly less (p less than 0.001) than in BALB/cJ mice, ranging from 48% in the mediobasal hypothalamus to 71% in the medial and dorsal hypothalamus. The number of TH-containing neurons was also significantly less in the CBA/J strain (p less than 0.001), ranging from 49% in the preoptic area to 74% in the mediobasal hypothalamus (MBH). With the exception of the MBH, enzyme activity per neuron was similar in both strains. In the MBH, strain differences in TH activity were greater than those for neuron number, resulting in less TH activity per neuron in the CBA/J strain. The results suggest that strain differences in the number of DA neurons are widespread and involve DA systems throughout the brain. Therefore, differences in whole brain TH activity cannot be attributed only to differences in specific regions. Our findings further support the view that the number of neurons of a specific chemical class may be under genetic control.     

Sociability and brain development in BALB/cJ and C57BL/6J mice

Sociability—the tendency to seek social interaction—propels the development of social cognition and social skills, but is disrupted in autism spectrum disorders (ASD). BALB/cJ and C57BL/6J inbred mouse strains are useful models of low and high levels of juvenile sociability, respectively, but the neurobiological and developmental factors that account for the strains’ contrasting sociability levels are largely unknown. We hypothesized that BALB/cJ mice would show increasing sociability with age but that C57BL/6J mice would show high sociability throughout development. We also hypothesized that littermates would resemble one another in sociability more than non-littermates. Finally, we hypothesized that low sociability would be associated with low corpus callosum size and increased brain size in BALB/cJ mice. Separate cohorts of C57BL/6J and BALB/cJ mice were tested for sociability at 19-, 23-, 31-, 42-, or 70-days-of-age, and brain weights and mid-sagittal corpus callosum area were measured. BALB/cJ sociability increased with age, and a strain by age interaction in sociability between 31 and 42 days of age suggested strong effects of puberty on sociability development. Sociability scores clustered according to litter membership in both strains, and perinatal litter size and sex ratio were identified as factors that contributed to this clustering in C57BL/6J, but not BALB/cJ, litters. There was no association between corpus callosum size and sociability, but smaller brains were associated with lower sociability in BALB/cJ mice. The associations reported here will provide directions for future mechanistic studies of sociability development.     

Alterations in expression of dopamine receptors and neuropeptides in the striatum of GTP cyclohydrolase-deficient mice

The hph-1 mice have defective tetrahydrobiopterin biosynthesis and share many neurochemical similarities with l-dopa-responsive dystonia (DRD) in humans. In both, there are deficiencies in GTP cyclohydrolase I and low brain levels of dopamine (DA). Striatal tyrosine hydroxylase (TH) levels are decreased while the number of DA neurones in substantia nigra (SN) appears normal. The hph-1 mouse is therefore a useful model in which to investigate the biochemical mechanisms underlying dystonia in DRD. In the present study, the density of striatal DA terminals and DA receptors and the expression of D-1, D-2, and D-3 receptors, preproenkephalin (PPE-A), preprotachykinin (PPT), and nitric oxide synthase (NOS) mRNAs in the striatum and nucleus accumbens and nigral TH mRNA expression were examined. Striatal DA terminal density as judged by specific [3H]mazindol binding was not altered while the levels of TH mRNA were elevated in the SN of hph-1 mice compared to control (C57BL) mice. Total and subregional analysis of the striatum and nucleus accumbens showed that D-2 receptor ([3H]spiperone) binding density was increased while D-1 receptor ([3H]SCH 23390) and D-3 receptor ([3H]7-OH-DPAT) binding density was not altered. In the striatum and nucleus accumbens, expression of PPT mRNA was elevated but PPE-A mRNA, D-1, D-2 receptor, and nNOS mRNA were not changed in hph-1 mice compared to controls. These findings suggest that an imbalance between the direct strionigral and indirect striopallidal output pathways may be relevant to the genesis of DRD. However, the pattern of changes observed is not that expected as a result of striatal dopamine deficiency and suggests that other effects of GTP cyclohydrolase I deficiency may be involved.     

Amphetamine-induced hypolocomotion in mice with more brain D2 dopamine receptors

The relationship between brain D₂ dopamine receptors and locomotor response to amphetamine was investigated in eight strains of mice. The D₂ receptor is defined as that dopaminergic site with high affinity (nanomolar) for neuroleptics and low affinity (micromolar) for agonists. D₂ receptors were measured in the striatum and olfactory tubercle using [³H]spiperone and 10 μM sulpiride to define specific binding. Four inbred strains of mice (CBA/J; C57BL/6J; DBA/2J; SEC/1ReJ) had low receptor densities of about 380 and 160 fmoles/mg protein in the striatum and olfactory tubercle, respectively; all these mice were essentially nonresponsive (i.e., locomotion) to low doses of amphetamine (0.5 and 1.0 mg/kg i.p.) or showed hyperlocomotion to high doses (5 mg/kg). Three other mouse strains (BALB/cJ; A/J; C3H/HeJ) had higher densities of about 600 and 230 fmoles/mg protein in the striatum and olfactory tubercle, respectively, and these mice all responded with hypolocomotion to the low doses and hyperlocomotion to the high dose of amphetamine. The two genetically different populations, one of which responded to amphetamine with hypolocomotion while the other did not, are analogous to hyperactive children, only 70% of whom respond to amphetamine-like drugs. Thus, the mice with high receptor density may serve as a model for studying the hyperactivity syndrome which may be associated with dopaminergic dysfunction.     

Mouse strain differences in locomotor,sensitisation and rewarding effect of heroin; association with alterations in MOP‐r activation and dopamine transporter binding

There is growing agreement that genetic factors play an important role in the risk to develop heroin addiction, and comparisons of heroin addiction vulnerability in inbred strains of mice could provide useful information on the question of individual vulnerability to heroin addiction. This study examined the rewarding and locomotor‐stimulating effects of heroin in male C57BL/6J and DBA/2J mice. Heroin induced locomotion and sensitisation in C57BL/6J but not in DBA/2J mice. C57BL/6J mice developed conditioned place preference (CPP) to the highest doses of heroin, while DBA/2J showed CPP to only the lowest heroin doses, indicating a higher sensitivity of DBA/2J mice to the rewarding properties of heroin vs C57BL/6J mice. In order to investigate the neurobiological substrate underlying some of these differences, the effect of chronic ‘intermittent’ escalating dose heroin administration on the opioid, dopaminergic and stress systems was explored. Twofold higher μ‐opioid receptor (MOP‐r)‐stimulated [³⁵S]GTPγS binding was observed in the nucleus accumbens and caudate of saline‐treated C57BL/6J mice compared with DBA/2J. Heroin decreased MOP‐r density in brain regions of C57BL/6J mice, but not in DBA/2J. A higher density of dopamine transporters (DAT) was observed in nucleus accumbens shell and caudate of heroin‐treated DBA/2J mice compared with heroin‐treated C57BL/6J. There were no effects on D₁ and D₂ binding. Chronic heroin administration decreased corticosterone levels in both strains with no effect of strain. These results suggest that genetic differences in MOP‐r activation and DAT expression may be responsible for individual differences in vulnerability to heroin addiction.     

Further evidence that a mouse Chromosome 4 locus influences cerebellar folial pattern

The cerebellar folial pattern of mice displays marks variation amomng inbred strains. Previous studies of progeny of crosses of C57BL/6 mice with DBA/2J and BALB/cByJ mice indicated a multifactorial mode of inheritance in both cases. The cross with DBA/2J led to the mapping, to Chromosome 4, of a locus (Cfp-1) that influences the frequency of the intraculminate fissure. Here we report that Cfp-1) influences the frequency of the declival sulcus and appears to influence the frequency of the intraculmiate and precentral fissures, in F₂ hybrid offspring from crosses of C57BL/6J and BALB/cByJ mice.     

Genetic determination of hypothalamic tyrosine hydroxylase activity in mice

Tyrosine hydroxylase (TH) activity data obtained from hypothalamic tissue samples of highly inbred mouse strains with known differences in their mesencephalic TH activity (BALB/cJ, C57BL/6ByJ, CXBI/ByJ), F1 hybrids and F2 generations were subjected to quantitative genetic analysis. No differences were observed between C57BL/6ByJ and CXBI/ByJ strains, but highly significant differences were found in hypothalamic TH activity between BALB/cJ and C57BL/6ByJ strains. Segregating genetic factors could not be detected in the replicate (C57BL/6ByJ X CXBI/ByJ) F2 generations, while the presence of segregating genetic units was indicated in the (C57BL/6ByJ X BALB/cJ)F2 population. Estimation of minimum number of genes and Elston's non-parametric one-locus test reveal that more genes are responsible for strain differences of TH activity in the hypothalamus compared to the dopaminergic areas of the mesotelencephalon. The results indicate that the heterogeneity of the catecholamine neuronal populations and terminal fields in the hypothalamus is reflected by the complex nature of the genetic control of TH activity in this brain region.     

Motor activity and the mesotelencephalic dopamine function. II. Multivariate analysis of genetically segregating generations.

Previous experiments on genetically different inbred strains of mice demonstrated parallel variations between the activity of regional brain tyrosine hydroxylase (TH) and locomotor behavior. Based on these associations, it was hypothesized that genetic variations in mesotelencephalic TH activity, an index of dopamine neurotransmitter function, would correlate positively with exploratory and locomotor behavior. In order to test this hypothesis, open-field motor behaviors and mesencephalic and striatal TH activities were analyzed by multivariate statistical methods in genetically segregating (C57BL/6ByJ X BALB/cJ)F2 and (C57BL/6ByJ X CXBI/ByJ)F2 generations. Factor analysis, based on correlation matrices of variables with significant genetic dominance or additive effects, demonstrated that locomotor activity and frequency of occurrence of various motor patterns were not correlated with mesencephalic and striatal TH activity. These results indicate that the assumption of a positive phenotypic correlation between spontaneous motor activity and mesotelencephalic TH activity does not hold in genetically segregating populations. Strategies and problems in revealing the behavioral consequences of genetically based variations in the mesotelencephalic DA system are briefly discussed.     

Multifaceted strain-specific effects in a mouse model of depression and of antidepressant reversal

Etiopathogenesis of depression and the cause of insensitivity to treatment remain poorly understood, although genetic makeup has been established as a contributing factor. The isogenicity of inbred mouse strains provides a useful tool for investigating the link between genes and behavior or drug response. Hence, our aim was to identify inbred mouse strains (among A/J, BALB/c, C3H, C57BL/6, CBA, DBA and FVB) sensitive to a 9-week period of unpredictable chronic mild stress (UCMS) and, from the fifth week onward, to the reversal effect of an antidepressant (AD) (imipramine, 20 mg/kg/day i.p.) on various depression-related changes: physical, behavioral and neuroendocrine states. UCMS induced a significant deterioration of the coat state (in all the strains), blunted emotional reactivity in the novelty-suppressed feeding (NSF) test (A/J, BALB/c, C57BL/6), and changes in the level of fecal corticosterone metabolites (BALB/c, C57BL/6, DBA, FVB). Imipramine treatment reversed the UCMS-induced alterations of the coat state (BALB/c, DBA), in the NSF test (A/J, BALB/c, C57BL/6) and in fecal corticosterone metabolites (BALB/c, C57BL/6). C3H, CBA and FVB mice were irresponsive to imipramine treatment. It is noteworthy that UCMS-induced physical or behavioral changes occurred without hypothalamo–pituitary–adrenal (HPA) axis alterations in some strains (A/J, C3H, CBA), although the AD-induced reversal of these changes in BALB/c and C57BL/6 was associated with HPA axis normalization. Finally, UCMS is shown to discriminate various alterations and to replicate in a strain-dependent manner diverse profiles reminiscent of human disease subtypes. UCMS may thus enable the selection of strains suitable for investigating specific depression-related features and could be an appropriate model for identifying genetic factors associated with increased vulnerability, specific symptoms of affective disorders, and AD resistance.     

In vivo and in vitro glycogenic effects of methionine sulfoximine are different in two inbred strains of mice

We investigated the relationship between brain glycogen anabolism and methionine sulfoximine (MSO)-induced seizures in two inbred mouse strains that presented differential susceptibility to the convulsant. CBA/J was considered a MSO-high-reactive strain and C57BL/6J a MSO-low-reactive strain. Accordingly, the dose of MSO needed to induce seizures in CBA/J mice is lower than that in C57BL/6J mice, and CBA/J mice which had seizures, died during the first convulsion. In addition, the time--course of the MSO effect is faster in CBA/J mice than that in C57BL/6J mice. Analyses were performed in C57BL/6J and CBA/J mice after administration of 75 (subconvulsive dose) and 40 mg/kg of MSO (subconvulsive dose, not lethal dose), respectively. In the preconvulsive period, MSO induced an increase in the brain glycogen content of C57BL/6J mice only. Twenty-four hours after MSO administration, the brain glycogen content increased in both strains. The activity and expression of fructose-1,6-bisphosphatase, the last key enzyme of the gluconeogenic pathway, were increased in MSO-treated C57BL/6J mice as compared to control mice, at all experimental time points, whereas they were increased in CBA/J mice only 24 h after MSO administration. These latter results correspond to CBA/J mice that did not have seizures. Interestingly, the differences observed in vivo were consistent with results in primary cultured astrocytes from the two strains. This data suggests that the metabolism impairment, which was not a consequence of seizures, could be related to the difference in seizure susceptibility between the two strains, depending on their genetic background.     

Use of a force-plate actometer for detecting and quantifying vertical leaping induced by amphetamine in BALB/cJ mice, but not in C57BL/6J, DBA/2J, 129X1/SvJ, C3H/HeJ, and CD-1 mice

The force-plate actometer is a relatively new computer-based instrument with high temporal and spatial resolution that has been used to measure the behavioral effects of genetic restriction (e.g., inbred mice) and drugs (e.g., dopaminergic agonists and antagonists) on a variety of behaviors in rodents, including locomotor activity, stereotypies, tremor, and wall rearing. In the present study, the force-plate actometer was used to measure the differential effects of amphetamine-induced (10.0mg/kg) vertical leaping in five inbred mouse strains (BALB/cJ, C57BL/6J, DBA/2J, 129X1/SvJ, and C3H/HeJ) and one outbred stock (CD-1). Across a 13-day, five-injection procedure, mice of the BALB/cJ strain leaped an average of 82 times per 60-min session; the C57BL/6J, DBA/2J, 129X1/SvJ, C3H/HeJ strains and CD-1 stock always showed zero or near zero levels of vertical leaping following amphetamine treatment. The quantitative precision afforded by the force-plate actometer revealed that the mean duration of the leaps by the BALB/cJ strain was 0.18 second, and the corresponding peak force averaged 87.4 gram per leap, which was more than 400% of the average body weight of this strain. Although no evidence of behavioral sensitization was indicated for amphetamine's effects on vertical leaping, sensitization to amphetamine's effects on spatial confinement (i.e., bouts of low mobility) was observed in all mouse types. Results indicate that the force-plate actometer is an instrument well suited for detecting and quantifying both vertical leaping and collateral behaviors induced by amphetamine in mice.     

Comparison of seizure phenotype and neurodegeneration induced by systemic kainic acid in inbred, outbred, and hybrid mouse strains

We assessed inbred, outbred and hybrid mouse strains for susceptibility to seizures and neurodegeneration induced by systemic administration of kainic acid (KA). Each strain showed a unique pattern of susceptibility to seizures as assessed by the dose necessary to induce continuous tonic clonic seizures, progression through six seizure levels, the number of mice that failed to satisfy seizure criteria, and seizure-induced mortality. In general, the C57BL/6, ICR, FVB/N, and BALB/c strains were resistant to seizures while the C57BL/10, DBA/2 J, and F1 C57BL/6*CBA/J strains were vulnerable. Neuronal cell death was quantified in four subfields of the hippocampus: CA3, the hilus of the dentate gyrus, CA1, and the dentate granule cell layer. Neurodegeneration was also semiquantitatively assessed in other brain regions including the neocortex, striatum, thalamus, hypothalamus and amygdala. Although there was variability in the extent of cell death within strains, there were significant differences in the amount of hippocampal cell death between strains and also different patterns of neurodegeneration in affected brain areas. In general, the C57BL/6, C57BL/10, and F1 C57BL/6*CBA/J strains were resistant to neurodegeneration while the FVB/N, ICR and DBA/2 J strains were vulnerable. The BALB/c strain was unique in that neurodegeneration was confined to the hippocampus. Consistent with previous findings, the resistant neurodegeneration phenotype was dominant in an F1 cross of resistant and vulnerable inbred strains. Our results, using a large number of mouse strains, definitively demonstrate that a mouse strain's seizure phenotype is not related to its neurodegeneration phenotype.