A timed intravenous pentylenetetrazol infusion scizure model for quantitating the anticonvulsant effect of valproic acid in the rat

A convulsive seizure model that utilizes timed intravenous infusions of pentylenetetrazol (PTZ) was developed to quantitate the magnitude of anticonvulsant effect in individual rats. PTZ was infused through an indwelling jugular vein catheter, and the threshold dose of PTZ was calculated from the time needed to produce clonic convulsions, the body weight of the animal, and the rate of infusion of the convulsant. The threshold dose of PTZ was determined in all animals 48 hr before and 15 min after anticonvulsant treatment. From theoretical considerations, the magnitude of anticonvulsant effect was defined as the logarithm of the posttreatment to pretreatment PTZ threshold dose ratio (log DR). The PTZ threshold was found to be insensitive to the rate of PTZ infusion and the body weight of the animal. Furthermore, the PTZ pretest did not influence the results of the posttest in animals treated with saline, and the interanimal variability in the PTZ threshold was found to be low (coefficient of variation of 12.2%). The PTZ infusion model was tested in a preliminary dose-response study of the anticonvulsant valproic acid (VPA). The ED₅₀ for VPA determined with PTZ infusion technique (76.1 ± 9.0 mg/kg) was in good agreement with a previous study that used the classical subcutaneous PTZ test. Since anticonvulsant effect is measured in individual, as opposed to groups, of animals, the PTZ infusion procedure may offer distinct advantages in the study of the pharmacodynamics of anticonvulsant compounds.