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Seizure susceptibility in DBA and C57 mice: the effects of various convulsants
1Department of Physiology, University of Utah School of Medicine, Salt Lake City 84108.
Abstract:
Convulsive dose 50s (CD50s) for various convulsive drugs and minimal and maximal electroshock seizure thresholds were determined in DBA and C57 mice. DBA mice had lower maximal electroshock seizure thresholds (MESTs, 15%) and CD50s for homocysteine thiolactone (HTL, 23%) and bicuculline (69%), and a higher CD50 for pentylenetetrazol (PTZ) at 3 weeks of age, the age of maximal audiogenic seizure (AGS) susceptibility. At 8 weeks, when DBA mice are not susceptible to AGSs, significant differences were a lower minimal electroshock seizure threshold (mEST, 37%) and maximal EST (MEST) (19%), lower CD50s for N-methyl-D-aspartate (NMDA) (39%), kainic acid (KA, 50%), HTL (32%), strychnine (37%), and a higher CD50 for nicotine (55%) in DBA mice. Based on these data it is suggested that pathways involving NMDA and KA receptors are responsible for increased susceptibility to seizure initiation (mEST), and are opposed by glycine pathways, and that opposing GABA and cholinergic systems at higher CNS levels are involved in seizure spread (AGSs and MEST) in these mice. Latency patterns indicate that nicotine, strychnine, PTZ and bicuculline have high blood-brain barrier (BBB) penetrability. Picrotoxin and the excitatory amino acid receptor agonists had longer latencies, suggesting low BBB penetrability. Age-related changes in latency, however, give evidence that difficulty in drug penetration of the BBB is not responsible for differences observed in CD50s between strains.
Insights
DBA mice show altered seizure susceptibility and drug responses compared to C57 mice, with differences linked to specific neurotransmitter pathways and blood-brain barrier penetration. These findings offer insights into seizure mechanisms.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Seizure thresholds and drug sensitivity can vary significantly between mouse strains.
- Understanding these differences is crucial for modeling neurological disorders and testing anticonvulsant therapies.
Purpose of the Study:
- To compare convulsive dose 50s (CD50s) and electroshock seizure thresholds between DBA and C57 mouse strains.
- To investigate the role of specific neurotransmitter systems and blood-brain barrier (BBB) penetration in observed strain-specific seizure responses.
Main Methods:
- Determination of minimal and maximal electroshock seizure thresholds in DBA and C57 mice.
- Measurement of CD50s for various convulsant drugs including homocysteine thiolactone (HTL), bicuculline, pentylenetetrazol (PTZ), N-methyl-D-aspartate (NMDA), kainic acid (KA), strychnine, nicotine, and picrotoxin.
- Analysis of drug latency patterns to assess BBB penetrability.
Main Results:
- DBA mice exhibited lower maximal electroshock seizure thresholds and CD50s for several drugs (HTL, bicuculline, NMDA, KA, strychnine) but higher CD50 for nicotine at different ages.
- Significant age-related differences in seizure thresholds and drug responses were observed between the strains.
- Latency data suggested varying BBB penetrability for different drugs, but this did not fully explain strain-specific CD50 differences.
Conclusions:
- Neurotransmitter pathways involving NMDA and KA receptors appear to mediate seizure initiation susceptibility in DBA mice.
- GABA and cholinergic systems at higher central nervous system (CNS) levels may be involved in seizure spread.
- Differences in BBB penetration do not solely account for the observed strain-specific drug responses in seizure models.