Genetic analysis of nicotine-induced seizures and hippocampal nicotinic receptors in the mouse.

A classical F2 and backcross genetic design was used to examine the relationship between sensitivity to nicotine-induced seizures and hippocampal nicotinic receptors. Nicotine was administered by i.v. infusion through cannulas implanted in the right jugular veins of mice from the C3H and DBA mouse strains and their derived F1, F2 and backcross (F1 X C3H and F1 X DBA) generations. Nicotine-induced seizure sensitivity was assessed by infusing nicotine at a 2.0 mg/kg/min concentration until the onset of a clonic seizure. After seizure testing, mice were sacrificed and the binding of alpha-bungarotoxin (BTX) was determined in three brain regions: cortex, midbrain and hippocampus. The pattern of results for the six generations for seizure sensitivity was similar to that observed for hippocampal BTX binding. Genetic analyses indicate that receptor concentrations in the hippocampus and seizure sensitivity are both influenced by a relatively simple genetic system which involves one or more genes acting in an additive fashion. In addition, the genetic correlation which is indicative of the extent to which two characters are influenced by the same genes, supports the relationship between nicotine-induced seizure sensitivity and hippocampal BTX binding. The results suggest that those animals which are sensitive to nicotine-induced seizures have a greater concentration of nicotinic receptors as determined by the binding of BTX than animals which are less sensitive to the convulsant effects of nicotine.