[Behavioral teratogenesis and placental, milk, and blood-brain barrier transfer following prenatal and postnatal exposures to chlorpromazine in rats].
In order to determine behavioral teratogenesis of fetal and neonatal exposures to chlorpromazine (CPZ) in rats, conditioned avoidance learning by shuttle box in pups was examined. CPZ was administered sc to pregnant and nursing rats during fetal organogenesis period (on days 11-15 of gestation, at doses of 9, 21 mg/kg/day), perinatal period (on days 16-20 of gestation, at 9, 18 mg/kg/day), and nursing period (on days 1-10 postpartum, at 9, 18 mg/kg/day). The results showed that high doses of CPZ during all periods caused learning impairment in pups, although learning impairment by the exposures during fetal organogenesis and nursing periods was stronger than that of perinatal exposure and pattern of learning impairment was different between the former and the latter. Exposure to CPZ during fetal organogenesis period induced an increase in norepinephrine and dopamine concentrations in the hippocampus of pups. Thus it is clear that developmental treatment with CPZ produced learning impairment. Furthermore, CPZ transferred rapidly into fetal and neonatal brains. Our results suggest that blood-brain barrier transfer of CPZ is a major factor in behavioral teratogenesis.
Watanabe
T
T
Drug Safety Research Center, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Matsuhashi
K
K
Takayama
S
S
D000818:Animals; D000831:Animals, Newborn; D001362:Avoidance Learning / Q000187:drug effects*; D015306:Biogenic Monoamines / Q000378:metabolism; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D002746:Chlorpromazine / Q000009:adverse effects* / Q000493:pharmacokinetics; D005260:Female; D008431:Maternal-Fetal Exchange; D008892:Milk / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains
D015306:Biogenic Monoamines; D002746:Chlorpromazine