PRENATAL CHLORPROMAZINE EFFECTS ON LIVER, SURVIVAL AND BEHAVIOR OF MICE OFFSPRING

¹ Laboratory of Neurochemistry, Cleveland Psychiatric Institute, and School of Medicine, Western Reserve University, Cleveland, Ohio

This multidisciplinary investigation was undertaken to evaluate prenatal chlorpromazine effects on pregnancy and behavior of the mother, as well as to examine possible teratogenic effects and hepatocellular alterations in relation to mortality, postnatal survival and changes in behavior of mice offspring. An evaluation of the placental transfer of S³⁵ CPZ revealed measurable amounts of unchanged CPZ and metabolites in liver and brain tissue of the offspring. A statistical evaluation of the prenatal effects of 4 and 16 mg/kg of CPZ revealed significant drug effects on delays between mating and birth, lowered maternal weight gains and decrements in maternal open field behavior, as well as decreases in litter size, offspring weight and significant increases in mortality at birth. A quantitative evaluation of prenatal CPZ effects on liver enzyme levels and glycogen content revealed elevated levels of leucine aminopeptidase (LAP-ase) activity, decreased alkaline phosphatase (ALK P-ase) activity and depletion of glycogen in the drug offspring at birth. A comparison of differences in the survival of drug and placebo offspring at 60 days revealed a significantly lower percentage of survival for the drug offspring independent of cross-fostering procedures. An evaluation of differences in the sex ratio of postnatal survival indicated a highly selective prenatal CPZ effect on postnatal survival of the female offspring. Comparisons of differences in the duration of hexobarbital action at 30 and 60 days after birth revealed significant differences between drug and placebo offspring. Significant differences were also observed in postnatal serum enzyme levels in SLAP-ase and ALK P-ase between drug and placebo offspring at 75 days after birth. At the behavioral level, offspring from mothers who received chlorpromazine during pregnancy made significantly fewer avoidances in shock-elicited escape-avoidance learning, traversed fewer squares in open field exploration, had longer open field latencies and made fewer wheel revolutions than the placebo offspring. In general, greater behavioral decrements were associated with the higher prenatal CPZ dose level. Finally, all of the prenatal drug effects on the offspring were modified by postnatal maternal residual drug effects and cross-fostering procedures, but they were not cancelled by such postnatal maternal influences.

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