Primidone-Induced Embryolethality and DRL Deficits in Surviving Offspring

Pregnant Sprague–Dawley rats were administered primidone (PRM) by oral gavage on gestation days 8–20 in doses of 0 or 120 mg/kg. This dose did not produce body weight differences in the dams during the dosing period nor were there differences in the birth weights of the offspring. PRM was embryolethal with only 43% of drug-treated dams maintaining their pregnancies, whereas 100% of the pregnant controls produced offspring. An analysis of resorption sites in PRM-treated dams that did not deliver showed a nearly identical number of implantation sites (12.6) compared to the litter size of controls (12.8) that delivered pups. There were no overall differences in exploratory activity levels between PRM-treated and control animals. However, in the PRM-treated females there was an absence of the sexually dimorphic increase in activity seen in control females when compared to control males. The PRM-treated males showed an impairment in the acquisition of a DRL-20 (differential reinforcement of low rates) operant schedule over a 9-week acquisition period. There were no differences in the total response rates between the groups, suggesting that this is a specific learning deficit and not a performance deficit. The results of these experiments provide evidence that prenatal PRM exposure can be embryolethal and also impair behavior in the surviving rat offspring.