Mouse strain variation in maximal electroshock seizure threshold

Maximal electroshock seizure threshold (MEST) is a classical measure of seizure sensitivity with a wide range of experimental applications. We determined MEST in nine inbred mouse strains and one congenic strain using a procedure in which mice are given one shock per day with an incremental (1 mA) current increase in each successive trial until a maximal seizure (tonic hindlimb extension) is elicited. C57BL/6J and DBA/2J mice exhibited the highest and lowest MEST, respectively, with the values of other strains falling between these two extremes. The relative rank order of MEST values by inbred strain (highest to lowest) is as follows: C57BL/6J > CBA/J = C3H/HeJ > A/J > Balb/cJ = 129/SvIMJ = 129/SvJ > AKR/J > DBA/2J. Results of experiments involving a single electroconvulsive shock given to separate groups of mice at different current intensities suggest that determination of MEST by the method used is not affected by repeated sub-maximal seizures. Overall, results document a distinctive mouse strain distribution pattern for MEST. Additionally, low within strain variability suggests that environmental factors which affect quantification of MEST are readily controlled under the conditions of this study. We conclude that MEST represents a useful tool for dissecting the multifactorial nature of seizure sensitivity in mice.     

Kindling Susceptibility and Genetic Seizure Predisposition in Inbred Mice

Olfactory bulb kindling rates were studied in two inbred strains of genetically seizure-prone mice (DBA/2 and El) and in three non-epileptic inbred strains [C57BL/6 (B6), ddY, and C3H/He (C3H)]. None of the DBA/2 mice had been stimulated to seizure before or during the kindling and all mice were studied at 4-6 weeks of age, before development of spontaneous or movement-induced seizure activity in the El strain. The audiogenically seizure-susceptible DBA/2 mice required the fewest number of stimulations to reach stage 5 seizure (mean +/- SE = 4.0 +/- 0.6). The nonepileptic C3H mice required the most stimulations to reach stage 5 seizures (22.6 +/- 1.4). Kindling rates for B6 (9.6 +/- 0.6), El (14.8 +/- 1.1), and ddY (18.5 +/- 1.0) strains were intermediate, and the kindling rate for each strain was significantly different from that of the other strains. These findings show that the seizure-susceptible El mouse kindles more rapidly than the genetically similar but nonepileptic ddY control and suggest that an inherited seizure susceptibility accelerates the kindling rate. Nonepileptic B6 mice kindled more rapidly than El mice, however, suggesting that genetic factors other than those that influence seizure susceptibility are of primary importance in the determination of the kindling rate.     

A pharmacogenetic evaluation of the role of local anesthetic actions in the cocaine kindling process.

Repeated administration of subconvulsant doses of lidocaine or cocaine results in the development of an increased susceptibility to seizures induced by the two drugs (pharmacological kindling). It has been hypothesized that the local anesthetic properties of cocaine are responsible for its convulsant and epileptogenic actions. As genetic factors appear to mediate acute sensitivity to the convulsant properties of cocaine and the development of cocaine-kindled seizures, the present studies used a pharmacogenetic approach to address this question further. The convulsant effects of lidocaine were evaluated in BALB, C57, DBA and SJL mice and compared with previous studies evaluating cocaine-induced seizures. We have also evaluated the development of lidocaine- versus cocaine-kindled seizures and the effects of repeated treatment with cocaine or lidocaine on subsequent lidocaine seizure susceptibility in three of these inbred mouse strains. As observed for cocaine, genetic factors influence the convulsant properties of lidocaine; however, the differences between the strains of mice in susceptibility to lidocaine-induced seizures (SJL greater than DBA = BALB = C57) did not parallel those seen for cocaine-induced seizures (C57 greater than DBA = BALB greater than SJL). Similarly, the time course for the expression of kindled seizures and the differences between the various inbred strains were not the same for lidocaine kindling and cocaine kindling. However, depending on the genetic background of the subject, the repeated administration of lidocaine, or cocaine, resulted in the development of sensitization or tolerance to the convulsant effects of lidocaine in an identical manner.(ABSTRACT TRUNCATED AT 250 WORDS)     

Physical activity enhances spatial learning performance with an associated alteration in hippocampal protein kinase C activity in C57BL/6 and DBA/2 mice

The effects of physical activity on spatial learning performance and associated hippocampal functioning were examined in C57BL/6Ibg (C57) and DBA/2Ibg (DBA) mice. C57 and DBA mice, 3 months of age, were subjected to 8 weeks of a physical activity regime (consisting of moderate-pace treadmill running 5 days/week, 60 min/day, 0% grade, 12 m/min) or remained sedentary in their cages. Mice were then tested on the Morris water maze task for 6 days followed by 12 days of testing on the place learning-set task (8 trials/day with each task). Both C57 and DBA run mice showed no difference in swim speed compared to controls. Hippocampal protein kinase C (PKC) activity was measured in cytosolic, loosely bound, and membrane-bound homogenate fractions. Mice subjected to the physical activity protocol were compared to sedentary controls from the same set of litters. Physical activity produced a 2- to 12-fold enhancement in spatial learning performance on both the Morris (P < 0.0001) and place learning-set (P < 0.02) probe trials in both C57 and DBA mice. DBA mice, which characteristically perform poorly in comparison to C57 mice, were enhanced to perform similarly to C57 control mice. This physical activity-induced enhancement in spatial learning performance was accompanied by alterations in hippocampal bound PKC activity (P < 0.05). These data provide further support for our previous hypothesis of a PKC activity involvement in spatial learning and enhancement of spatial learning performance in rodents by physical activity. In addition, these data indicate that hippocampal PKC activity may be involved in the physical activity-induced enhancement of spatial learning performance.     

Hippocampal protein kinase C activity is reduced in poor spatial learners

Activation of protein kinase C (PKC) via neurotransmitter coupling processes has been associated with long-term potentiation (LTP) or classical conditioning, but whether natural variation in PKC activity affects learning performance remains to be determined. Inbred strains of mice differ in their ability to exhibit spatial reference memory as measured by the Morris water task. C57BL/6Ibg (C57) mice perform the task better than DBA/2Ibg (DBA) mice, which show relatively little spatial preference. Hippocampal PKC activity extracted from the particulate fraction was lower in DBA mice than in C57 mice. To examine the potential relationship of PKC activity with spatial learning performance, 11 C57BL/6J × DBA/2J recombinant inbred strains (BXD RIs) were trained in the place learning version of the Morris water task. Cortical and hippocampal PKC activities were measured. Variation in spatial learning performance and PKC activity from cortex and hippocampus was observed. A positive significant correlation was observed between measures of spatial learning accuracy and hippocampal PKC in these strains. No correlation was observed between spatial learning accuracy and cortical PKC activity. These data suggest that animals with lower hippocampal PKC activity may have problems performing spatial reference memory tasks with the same degree of accuracy as those with higher hippocampal PKC activity.     

Enhancement of hippocampally-mediated learning and protein kinase C activity by oxiracetam in learning-impaired DBA/2 mice

The effects of oxiracetam on hippocampally-mediated learning performance and hippocampal protein kinase C (PKC) were examined in C57BL/6Ibg (C57) and DBA/2Ibg (DBA) mice. C57 and DBA mice were subjected to daily injections of oxiracetam (50 mg/kg i.p.) or vehicle (0.9% saline) for a total of 9 days. C57 and DBA mice were examined on a modified version of the Morris water maze task and the contextual fear conditioning task on the last 5 or 2 days, respectively, of the 9-day treatment schedule. When compared with controls, C57 and DBA oxiracetam-treated mice showed no difference in motor skill capability to perform these complex learning tasks (swim speed or ability to freeze). Hippocampal PKC activity was measured in cytosolic, loosely-bound, and membrane-bound homogenate fractions. Oxiracetam-treated DBA mice demonstrated a significant increase in spatial learning performance as determined by the Morris task. DBA performance was also improved in contextual learning as determined by the fear conditioning task. The increase in spatial learning performance was correlated to an increase in membrane-bound PKC. No substantial improvements in C57 mice were observed on either learning task nor did hippocampal PKC activity change in response to oxiracetam treatment. These data demonstrate that the learning impairment of DBA mice can be reversed by treatment with a nootropic agent and support previous studies suggesting that PKC may be one mechanism of action for oxiracetam.     

Epileptogenesis induced by rapidly recurring seizures in genetically fast- but not slow-kindling rats

A brief period of rapidly recurring hippocampal seizures can lead to the progressive development of a permanent increase of seizure susceptibility over several weeks, so-called ‘delayed kindling'. We have analyzed seizure parameters critical for the induction of delayed kindling in two strains of rats characterized by fast and slow rates of traditional kindling, respectively. Forty seizures were produced during about 3 h by electrical kindling stimulations every 5 min in the ventral hippocampus. The fast rats displayed several generalized convulsions and had long periods of epileptiform activity, whereas the slow animals only exhibited brief, focal seizures. Changes in excitability were determined after 4 weeks using five test stimulations, and 2 weeks later by subjecting all animals to traditional hippocampal kindling. The fast rats showed clearly enhanced responsiveness at these time points, whereas no evidence of permanently increased seizure susceptibility was obtained in the slow rats. Our data indicate that the long-lasting stimulus-evoked seizures are mainly responsible for inducing delayed kindling, whereas the number of seizure events or generalized convulsions, and the total duration of epileptiform activity are less important. We hypothesize that long seizure episodes may be necessary to trigger the cascade of gene changes regulating the development of epilepsy.     

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.     

Amygdala-kindled and pentylenetetrazole-induced seizures in glutamate transporter GLAST-deficient mice

The glutamatergic system has been shown to be important for the induction of epileptiform activity and the development of epileptogenesis. To investigate the role of the astroglial glutamate transporter GLAST in epileptogenesis, we examined amygdala (AM)-kindled and pentylenetetrazole (PTZ)-induced seizures in GLAST-deficient mice (GLAST(-/-)) and compared them to those observed in wild-type mice (GLAST(+/+)) and maternal C57Black6/J (C57) mice. AM-kindling resulted in no significant differences in afterdischarge threshold or in the seizure responses induced by first stimulation between these groups. In addition, although no significant differences were seen in kindled seizure development, the generalized seizure duration of AM-kindled seizures in GLAST(-/-) mice was significantly prolonged (approximately 35%) compared with that of C57 mice. Furthermore, GLAST(-/-) mice showed more severe stages of PTZ-induced seizures than GLAST(+/+) mice, and the latency to the onset of seizures was significantly shorter for the mutant mice. These results indicate that GLAST is one of factors determining seizure susceptibility.     

Strain differences in the development of susceptibility to audiogenic seizures after acoustic priming but not after hearing loss

Either exposure to an initial auditory stimulus (IAS) or external ear plugging (EEP) was used to produce susceptibility to audiogenic seizures in C57BL/6Bg and DBA/1Bg mice. After the IAS, increments in seizure susceptibility occurred by 5 h in C57BL/6Bg mice and by 24 h in DBA/1Bg-ras mice, whereas after EEP, increments in seizure susceptibility occurred by 48 h in C57BL/6Bg and by 24 h in DBA/1Bg-ras mice. Because both the IAS and EEP produce hearing loss, the strain differences in the effect of the IAS on the development of susceptibility and the strain similarities in the effect of the EEP on the development of susceptibility support the hypothesis that acoustic priming in the C57BL/6Bg at 19 days of age involves another mechanism in addition to that of hearing loss and disuse supersensitivity. It was suggested elsewhere that the other mechanism is mediated by a post-IAS decrease in the concentration of brain γ-aminobutyric acid and requires brain protein synthesis for a brief period post-IAS.     

Mechanism of electrographic seizure generation in the hippocampal slice in Mg2+-free medium: the role of GABAa inhibition

We recently have described a new model of ictal-like electrographic activity in the hippocampal slice. When magnesium is eliminated from the medium bathing the hippocampal slice, spontaneously occurring electrical events which closely resemble electrographic seizures can be recorded extracellularly from area CA3. In order to begin to understand the mechanisms of initiation and termination of these seizures, the present study investigated the role of GABAa-mediated inhibition in these processes. Prior to the onset of a seizure recorded from stratum pyramidale of CA3, a twin-pulse stimulus to stratum radiatum of CA3 evoked twin EPSPs. Following the seizure, the same stimulation triggered a strong epileptiform burst. This is consistent with the known reduction of GABAa inhibition after seizures in vivo. Addition of bicuculline, picrotoxin, or penicillin, which reduce the efficacy of GABAa-mediated inhibition in this system, caused triggered epileptiform bursting to occur prior to the seizure as well. They also lowered the threshold for the production of seizures, facilitating their spontaneous occurrence or elicitation by fewer stimulus pulses. This suggests that the GABAa inhibition present in magnesium-free (0-Mg) plus baclofen medium tends to suppress the onset of seizures and raises the seizure threshold. However, these drugs did not prolong the ictal events. This suggests that in this model, GABAa-mediated inhibition is not responsible for termination of the seizure-like activity. Although there is some potentiation of the tonic firing phase of the seizures under these conditions, there is no gross change in the morphology of the events when inhibition is suppressed. In this model, therefore, GABAa-mediated inhibition plays a limited role in determining the structure and duration of the ictal events, but may contribute to the seizure threshold.     

Region-specific modulation of limbic seizure susceptibility by ovarian steroids

Gonadal steroid hormones can markedly affect seizure susceptibility. Ovariohysterectomized female rats given ovarian steroid hormone supplements were used to evaluate the effects of ovarian steroids on epileptiform activity in hippocampal slices in vitro and on flurothyl-induced seizures in vivo. Seizure susceptibility was compared in the entorhinal cortex (EC) and CA1 regions of the hippocampus perfused with Mg(2+)-free medium, which leads to epileptiform discharges caused by a relief of voltage-dependent NMDA receptor block. After in vivo treatment with 500 microg of progesterone for 2 h prior to slice preparation, the latency to onset of low Mg(2+)-induced epileptiform activity of slices was significantly prolonged compared to slices from controls. In contrast, progesterone replacement accelerated the development of epileptiform activity in the CA1 region. Neither estrogen alone (2 x 2 microg of estradiol benzoate, 48 and 24 h prior to the experiment), nor a combined treatment with estrogen plus progesterone, significantly affected seizure susceptibility in either CA1 or the EC. There were no consistent effects of estrogen or progesterone, alone or in combination, on flurothyl-induced seizures in vivo. The data suggest that in vitro, progesterone alters seizure susceptibility in a site- and seizure model-specific fashion. The differential effects of progesterone may be due to differential expression of progesterone receptor isoforms or metabolites in specific brain areas suggesting that selective modulation of NMDA receptor-dependent epileptiform activity may play a role in hormonal effects on epileptogenesis.     

Kainate and AMPA receptor binding in seizure-prone and seizure-resistant inbred mouse strains

Glutamate and its receptors represent the major excitatory neurotransmission system in the mammalian brain and are considered important in the pathogenesis of many neurological diseases. The present study describes saturation binding experiments performed to measure the affinity (K_d) and density (B_max) of kainate and AMPA receptors in striatum, cortex and hippocampus from mature DBA/2J (DBA) and C57BL/6J (C57) mice. Previous studies have documented that these two strains differ significantly in seizure susceptibility, with DBA mice exhibiting greater sensitivity in various convulsant tests compared to C57 mice. Non-linear regression analysis of binding data together with Student's t-test and ANOVA revealed significantly higher densities of kainate receptors in striatum and of AMPA receptors in cortex of DBA mice. C57 mice exhibited higher striatal [³H]AMPA binding. There were no significant differences between the mouse strains in binding sites prepared from hippocampus and no differences in affinity for either receptor in any brain region studied. The results support a role for kainate and AMPA receptors in seizure sensitivity, possibly by influencing glutamate transmission in specific pathways. It is unlikely, however, that these receptors account for the generation of seizures alone but rather cooperate with other glutamatergic and non-glutamatergic neurotransmitter systems.     

c-Fos immunohistochemical mapping of the audiogenic seizure network and tonotopic neuronal hyperexcitability in the inferior colliculus of the Frings mouse

The Frings mouse is a model of audiogenic seizure (AGS) susceptibility. The genetic locus responsible for the AGS phenotype in the Frings mouse has been named monogenic audiogenic seizure-susceptible (MASS1). MASS1 is unique in that it is one of only two identified seizure loci that are not associated with an ion channel mutation. Furthermore, Frings mice display a robust AGS phenotype demonstrating very high and prolonged susceptibility to sound-induced tonic extension seizures. The purpose of this investigation was to use c-Fos immunohistochemistry to map the brain structures involved in the Frings AGS and to examine neuronal hyperexcitability in the inferior colliculus, the brain structure that is recognized as the site of AGS initiation. AGS mapping revealed that intense seizure-induced neuronal activation was mostly limited to structures involved in a brainstem seizure network, including the external and dorsal nuclei of the inferior colliculus, as observed in other AGS rodents. Acoustically induced c-Fos expression in the central nucleus of the inferior colliculus to sub-AGS threshold tone stimulations displayed a greater level of neuronal activation in AGS-susceptible Frings, DBA/2J and noise-primed C57BL/6J mice compared to AGS-resistant C57BL/6J and CF1 mice. The AGS-susceptible mice also displayed c-Fos immunoreactivity that was more focused within the tonotopic response domain of the inferior colliculus compared to AGS-resistant mice. Furthermore, Frings mice displayed significantly greater tonotopic hyper-responsiveness compared to other AGS-susceptible mice.     

Synaptosomal high-affinity noradrenaline uptake does not differ between mice susceptible (DBA/2J) and resistant (C57 BL/6) to audiogenic seizures

Abnormalities in noradrenaline-mediated neurotransmission have been advocated as a basis of the age-related susceptibility of DBA/2J mice to generalised convulsions induced by auditory stimulation. We have measured the kinetics of synaptosomal high-affinity noradrenaline uptake in 5 brain regions of DBA/2J mice at ages before, during and after their maximal susceptibility to audiogenic seizures, and age-matched C57 BL/6 mice, a strain resistant to audiogenic seizures at all ages. No differences were found between the two strains of mice in any of the brain regions studied. Abnormalities of high-affinity noradrenaline uptake do not contribute to audiogenic seizure susceptibility of DBA/2J mice.     

Strain comparisons and developmental profile of the delta subunit of the murine GABAA Receptor

GABA_A receptors are multisubunit inhibitory chloride channels in the brain which open in response to binding of -γ-aminobutyric acid (GABA) and are thought to be involved in some forms of seizures. We compare the sequence and expression of the GABA_A receptor δ subunit in audiogenic seizure prone (DBA/2J) and seizure resistant (C57BL/6J) inbred strains of mice and also report this subunit's postnatal developmental profile. We did not detect any unique features in the 6 subunits of DBA/2J mice which might explain their seizure susceptibility, but did detect in some clones from both DBA/2J mice and C57BL/6J mice an unusual substitution of His for a conserved Tyr in the δ subunit's first putative transmembrane region.     

Differential Susceptibility to Seizures Induced by Systemic Kainic Acid Treatment in Mature DBA/2J and C57BLl6J Mice

Summary: Mature DBA/2J (D2) and C57BL/6J (B6) mice aged P.10 weeks were studied to determine susceptibility to behavioral seizures induced by kainic acid (KA) and the possible influence exerted by differences in metabolism and blood-brain barrier (BBB) transport. Mice were observed for 4 h after subcutaneous (s.c.) KA injection. Behavioral seizure parameters included latency to first seizure (clonus), latency to tonic/clonic seizure, and latency to status epilepticus (SE). At a KA dose of 25 mg/kg, 80% of D2 mice exhibited tonicklonic seizures, whereas all B6 mice remained seizure-free. At 30 mg/kg, tonic/ clonic seizures were observed in 100% of D2 mice and 25% of B6 mice. Of D2 mice exhibiting at least one clonic seizure in response to KA at a dose of 25 mg/kg, 50% entered SE and eventually died. Administration of [³H]KA (6.6 × 10⁶dpm) at doses of 25 mg/kg (convulsive) or 11.1 μ/g (nonconvulsive) to mice of both strains resulted in similar levels of radioactivity in cortex, hippocampus, and cerebellum 30 and 60 min after injection. Bioconversion of [³H]KA to a radiolabeled brain metabolite in vivo could not be documented in mice from either strain. Results confirm previously reported differences between D2 and B6 mice in their relative susceptibility to seizures induced by systemic KA administration and suggest that these differences are not related to strain-specific variation in metabolism or BBB transport of KA. Further studies of these two strains of mice may be useful for investigating genetic influences upon seizure susceptibility.     

Strain comparisons and developmental profile of the delta subunit of the murine GABAA receptor.

GABAA receptors are multisubunit inhibitory chloride channels in the brain which open in response to binding of gamma-aminobutyric acid (GABA) and are thought to be involved in some forms of seizures. We compare the sequence and expression of the GABAA receptor delta subunit in audiogenic seizure prone (DBA/2J) and seizure resistant (C57BL/6J) inbred strains of mice and also report this subunit's postnatal developmental profile. We did not detect any unique features in the delta subunits of DBA/2J mice which might explain their seizure susceptibility, but did detect in some clones from both DBA/2J mice and C57BL/6J mice an unusual substitution of His for a conserved Tyr in the delta subunit's first putative transmembrane region.     

Heterosis and resistance to DFP effects on spatial learning in C57BL X DBA hybrids

The inbred mouse strains C57BL/6Ibg and DBA/2Ibg differ in their ability to exhibit spatial learning in the Morris water task. C57BL mice learn the task well and show impairment of spatial learning following disruption of cholinergic function. DBA mice show rudimentary spatial learning ability, and are not further impaired when cholinergic function is decreased. These mice may carry genes regulating a noncholinergic spatial learning system. To test this hypothesis, first generation (F1) hybrids between DBA and C57BL mice were tested for spatial learning in the Morris water task. The hybrids performed better than either parental strain, suggesting that both parents contributed genes for spatial learning ability. Chronic treatment with diisopropylfluorophosphate (DFP), which abolished spatial learning ability in C57BL mice, produced only minor impairments in the hybrids. The behavioral resistance to DFP occurred despite significant reductions in hippocampal and cortical muscarinic binding. The results suggest either that the hybrids inherited a noncholinergic neurochemical system influencing spatial learning from their DBA parents or that the DFP treatment did not disrupt cholinergic function to a sufficient degree to impair the superior learning abilities of the F1 hybrids.     

Acute and Chronic Acetazolamide Administration in DBA and C57 Mice: Effects of Age

The clinical utility of the carbonic anhydrase (CA) inhibitor acetazolamide (ACTZ) is limited because of rapid development of tolerance to its effects. Tolerance is thought to develop as a result of glial cell proliferation and/or increased CA synthesis. DBA mice, susceptible to audiogenic seizures (AGSs) in an age-dependent manner, have increased CA activity as compared with C57 (non-audiogenic seizure susceptible) mice at 21 and 110 days of age. The present work utilized ACTZ to help determine the relationship between increased CA activity in brain and AGSs in DBA mice. Also, minimal electroshock seizure threshold (EST) was measured at various ages in DBA and C57 mice to determine age-related changes in CNS excitability. EST was significantly lower in DBA as compared with C57 mice at 18 days and between 40 and 115 days of age, suggesting that DBA mice remain hyperexcitable to electrical stimulation after they develop resistance to AGSs. ACTZ ED50s against maximal electroshock seizures (MES) were significantly higher in DBA as compared with C57 mice at 26,36, and 115 days of age. This finding correlates with higher CA activity in this strain at 110 days of age, noted previously. However, at 21 days of age, when CA activity is also higher in DBA versus C57 mice, there were no significant differences in ACTZ ED50s against MES between the strains. ACTZ ED50s against AGSs in DBA mice were considerably lower than ACTZ ED50s against MES in either strain, suggesting that a particular fraction of CA is intimately involved in the production of AGSs.(ABSTRACT TRUNCATED AT 250 WORDS)