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Genetic correlations among inbred strain sensitivities to convulsions induced by 9 convulsant drugs
1Department of Physiology and Biophysics, Hahnemann University, Philadelphia, PA 19102.
Abstract:
Inbred mouse strains differed significantly in sensitivity to convulsions induced by 9 convulsant drugs administered using a timed infusion procedure. Some strains (e.g. BALB/cJ, A/J) were generally seizure-susceptible, while some were generally seizure resistant (e.g. C57BL/6J, SWR/J). However, the overall pattern of strain sensitivities was complex, and depended upon drug and convulsant sign. Five of the drugs (bicuculline, DMCM, picrotoxin, TBPS and pentylenetetrazol (PTZ] produce convulsions, at least in part, through their interactions with the GABA receptor, while the other 4 (strychnine, CHEB, 4-aminopyridine and kainic acid) act through independent mechanisms. We predicted that responses to drugs with similar mechanisms of action would be genetically correlated. However, strains sensitive to picrotoxin-induced convulsions were not necessarily sensitive to convulsions elicited by PTZ or TBPS. Furthermore, different convulsant signs produced by a single drug were not always strongly correlated. Instead, genetic correlations were found among inbred strains for sensitivity to similar convulsant signs produced by different drugs. This suggests that genetic variation in sensitivity to these convulsant drugs arises primarily from variation in systems important for the expression of the convulsion.
Insights
Genetic differences in mouse strains influence seizure susceptibility to various convulsant drugs. Strain sensitivity patterns were complex, suggesting genetic factors impact convulsion expression systems rather than specific drug mechanisms.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Inbred mouse strains exhibit varying responses to centrally acting drugs.
- Understanding genetic influences on seizure susceptibility is crucial for neurological research.
Purpose of the Study:
- To investigate genetic correlations in seizure susceptibility across different inbred mouse strains using various convulsant drugs.
- To determine if drug mechanism of action or convulsion sign is a stronger predictor of genetic correlation.
Main Methods:
- Administered nine convulsant drugs via timed infusion to multiple inbred mouse strains.
- Assessed strain-specific sensitivity and recorded various convulsant signs.
- Analyzed genetic correlations between strain sensitivities to different drugs and convulsion types.
Main Results:
- Significant differences in seizure susceptibility were observed among inbred mouse strains.
- Strain sensitivity patterns were complex and drug-dependent, not always aligning with drug mechanisms of action.
- Genetic correlations were stronger for similar convulsion signs induced by different drugs, rather than for drugs with similar mechanisms.
Conclusions:
- Genetic variation in convulsant drug sensitivity is primarily linked to systems involved in convulsion expression.
- The study highlights the complexity of genetic influences on seizure disorders.
- Findings suggest focusing on convulsion-phenotype-based genetic correlations for future research.