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Mature male and female mice from six inbred stains were tested for susceptibility to behavioral seizures induced by a single injection of cocaine. Cocaine was injected ip over a range of doses (50-100 mg/kg) and behavior was monitored for 20 minutes. Seizure end points included latency to forelimb or hindlimb clonus, latency to clonic running seizure and latency to jumping bouncing seizure. A range of strain specific sensitivities was documented with A/J and SJL mice being most sensitive and C57BL/6J most resistant. DBA/2J, BALB/cByJ and NZW/LacJ strains exhibited intermediate sensitivity. EEG recordings were made in SJL, A/J and C57BL/6J mice revealing a close correspondence between electrical activity and behavior. Additionally, levels of cocaine determined in hippocampus and cortex were not different between sensitive and resistant strains. Additional studies of these murine strains may be useful for investigating genetic influences on cocaine-induced seizures.

Mature DBA/2J (D2) mice are very sensitive to seizures induced by various chemical and physical stimuli, whereas C57BL/6J (B6) mice are relatively seizure resistant. We have conducted a genome-wide search for quantitative trait loci (QTLs) influencing the differential sensitivity of these strains to kainic acid (KA)-induced seizures by studying an F2 intercross population. Parental, F1, and F2 mice (8-10 weeks of age) were injected subcutaneously with 25 mg/kg of KA and observed for 3 h. Latencies to focal and generalized seizures and status epilepticus were recorded and used to calculate an overall seizure score. Results of seizure testing indicated that the difference in susceptibility to KA-induced seizures between D2 and B6 mice is a polygenic phenomenon with at least 65% of the variance due to genetic factors. First-pass genome screening (10-cM marker intervals) in F2 progeny (n = 257) documented a QTL of moderate effect on Chromosome (Chr) 1 with a peak LOD score of 5.5 (17% of genetic variance explained) localized between D1Mit30 and D1Mit16. Provisional QTLs of small effect were detected on Chr 11 (D11Mit224-D11Mit14), 15 (D15Mit6-D15Mit46) and 18 (D18Mit9-D18Mit144). Multiple locus models generally confirmed the Mapmaker/QTL results and also provided evidence for another QTL on Chr 4 (D4Mit9). Multilocus analysis of seizure severity suggested that additional loci on Chrs 5 (D5Mit11), 7 (D7Mit66), and 15 (D15Nds2) might also contribute to KA-induced seizure response. Overall, our results document a complex genetic determinism for KA-induced seizures in these mouse strains with contributions from as many as eight QTLs.

Mature DBA/2J (D2) and C57BL/6J (B6) mice aged 9-10 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 tonic/clonic 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 x 10(6) dpm) at doses of 25 mg/kg (convulsive) or 11.1 micrograms (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.

This study reports comparative dose-response data for kainic acid (KA) induced seizures in juvenile (35-40 days old) and adult (70-90 days old) Wistar-Furth (WF), Fisher 344 (F344), Sprague-Dawley (SD) and Long-Evans Hooded (LEH) rats. Juvenile male WF (n = 51), F344 (n = 55), SD (n = 60), LEH (n = 50) and adult male WF (n = 48), F344 (n = 52), SD (n = 52), LEH (n = 53) rats were given KA 6, 8, 10, 12 or 14 mg/kg, sc. As previously demonstrated adult WF and F344 rats showed the greatest sensitivity and most reliable convulsant responses to kainic acid; SD and LEH rats were less sensitive and showed more variable convulsant responses. Regardless of strain, all juvenile rats exhibited greater sensitivity and less variable convulsant response to KA compared to adults. This was most evident in juvenile SD and LEH rats. Results suggest that while seizure sensitivity to KA decreases with age, genetic factors may regulate the expression of this resistance.

The aim of this study was to characterize interactions between striatal kainate (KA) receptors and dopamine (DA) release using in vivo microdialysis. After insertion of a microdialysis probe and establishment of baseline DA release, each preparation was standardized with a pulse of an iso-osmotic solution of 100 mM KCl in Ringer's solution. DA release following pharmacological manipulation was compared to potassium-induced release and expressed as a percent value. In one group of animals, KA (12.5 mM in Ringer's solution) was administered via the microdialysis probe in 2, 3, 5 or 10 min pulses 30 min following standardization with potassium resulting in release of DA which was 15.7 +/- 3.9, 30.3 +/- 11.3, 67.5 +/- 15.0 and 92.9 +/- 19.8% of potassium-induced DA release, respectively. Perfusion of CdCl2 (0.6 mM in Ringer's solution) 30-45 min prior to a 10 min KA pulse significantly reduced KA-induced DA release compared to control values. Intrastriatal administration of kynurenate (Kyn) attenuated KA-induced DA release in a dose-dependent manner. Levels of DA metabolites in striatal perfusates were significantly reduced following KA administration. This effect was partially reversed by cadmium pretreatment but not affected by Kyn pretreatment. Findings of this study indicate that KA induces striatal DA release in a dose-dependent manner, and this effect is at least partially dependent upon activation of calcium channels. Results also indicate dose-dependent inhibition of KA-induced striatal DA release by the excitatory amino acid receptor antagonist, Kyn, suggesting that this compound interacts with striatal KA receptors and that these receptors are involved with modulating striatal DA release in vivo.

We describe a strain of rats (Wistar-Furth) that is highly susceptible to the neurotoxic effects of kainic acid (KA) and presents a reliable and quantifiable (with low within-group variability) animal model of status epilepticus. Wistar-Furth rats are more sensitive and demonstrate a less variable convulsant response than Sprague-Dawley and Long-Evans rats when tested for total time in seizure activity, latency to onset of first seizure, latency to status epilepticus, seizure severity scores, and percentage exhibiting behavioral seizures and status epilepticus. Results suggest that significant heterogeneity exists in the rodent population with regard to neuronal sensitivity to an excitotoxic amino acid and indicate that strain differences are an important consideration in studies using KA.

The time course and severity of the excitotoxic syndrome induced in rats by s.c. injection of 10 mg/kg kainic acid (KA) was modified by pretreatment with MK801, a non-competitive inhibitor of the NMDA receptor, at doses of 0.1, 1 and 10 mg/kg. A dose-dependent increase in the severity of the KA-induced electrographic (EEG) manifestations of epilepsy was seen after MK801. This consisted of an earlier appearance and higher number of EEG seizures, longer time spent in seizures, and an earlier onset of status epilepticus. In contrast, behavioral seizures were increased only in the 0.1 mg/kg MK801 group, but abolished by higher doses. On the contrary, wet dog shakes were progressively reduced with increasing doses of MK801. Four of the 9 animals receiving KA-only group and 3 of the 10 animals in the 1 and 10 mg MK801 groups were sacrificed 5 days after KA. The brain of the KA-only rats presented diffuse gross and microscopic evidence of hemorrhagic necrosis and neuronal damage; the MK801 rats showed only minimal neuronal loss in the CA3 hippocampal sector. This study demonstrates that neuronal damage and epileptiform activity can be dissociated. Furthermore, it confirms the protective effect of MK801 against neuronal damage caused by multiple factors. Lastly, it emphasizes the need for EEG monitoring in order to accurately assess any epileptic/antiepileptic effect.

Pretreatment of rats with homotaurine (3 aminopropanesulfonic acid; 3APS), a synthetic gamma-aminobutyric acid (GABA) analog, protected from the convulsant and cytotoxic action of systemically injected kainic acid (KA). Wet dog shaking (WDS) behavior was significantly reduced. Taurine, an inhibitory non-GABA-mimetic amino acid, and muscimol (another direct GABA-agonist) reduced the number of seizures and lesions in the brain but were less effective than homotaurine. Progabide (a GABA-agonist) did not modify kainic acid effects. The neurotoxicity of kainic acid could have been due to repetitive convulsive activity. Activation of GABA-mediated inhibition is an effective, but not the determinant means of preventing KA-induced abnormalities.