NEURAL SENSITIVITY TO PENTYLENETETRAZOL CONVULSIONS IN INBRED AND SELECTIVELY BRED MICE

In these experiments, sensitivity to the convulsant drug pentylenetetrazol (PTZ) was measured in 10 inbred mouse strains, and in 4 mouse lines selectively bred for severe (WSP1, WSP2) or minimal (WSR1, WSR2) ethanol withdrawal convulsions. Using a timed infusion procedure, sensitivity to convulsions was assessed by measures of latency to convulsion, effective dose (ED) infused at time of convulsion, and brain concentration (BC) of PTZ at time of convulsion. In addition, ED and latency to convulsion were measured in WSP and WSR mice at 5 different concentrations of PTZ. Higher concentrations, which increased rate of drug infusion, reduced latency but had little effect on ED. WSP1 mice were slightly more sensitive to PTZ than WSR] mice, but WSP2 mice were equally or less sensitive than WSR2 mice. Among the inbred strains, latency, ED and brain PTZ concentration were found to be highly correlated, suggesting that pharmacokinetic factors do not significantly influence access of PTZ to sites of action in the central nervous system. The C57BL/6J strain was least sensitive by all measures, while DBA/2J mice were highly sensitive. The BALB/cJ strain was the most sensitive strain as assessed by ED and latency, but BC indicated relatively average sensitivity. Apparently, pharmacokinetic factors in this strain result in a relatively rapid accumulation of drug in brain, making it appear to be more sensitive. Thus, although ED provides a reliable estimate of neural sensitivity in general, genetic factors exist which, in some strains, modify access of PTZ and possibly other drugs to brain, potentially affecting determination of sensitivity in the absence of a measure of brain drug concentration.