Prenatal neuroleptic exposure and growth stunting in the rat: an in vivo and in vitro examination of sensitive periods and possible mechanisms.
There is increasing evidence that a number of neurotransmitters can play a trophic role in the development of the central nervous system. Dopamine is one candidate for this role. In a series of papers, Lewis, Patel, and colleagues have demonstrated that exposure to compounds which interfere with dopaminergic neurotransmission ("neuroleptics") can block cell proliferation in the brains of 11-day-old rat pups for at least 24 hr. More recently our laboratory has reported that prenatal exposure to haloperidol (HAL), a neuroleptic which binds to and blocks dopamine receptor sites in the adult brain, permanently stunts body and brain growth when that exposure extends throughout postimplantation pregnancy. Reported here are the results of two experiments conducted to further examine this phenomenon. The first experiment attempted to identify sensitive gestational periods for the HAL effect on growth in vivo. This experiment also assessed the effect of exposure to reserpine (RES), a compound which in the adult blocks dopaminergic neurotransmission by rupturing monoamine storage vesicles, an effect which is quite distinct from the HAL mechanism of action. In a second experiment, gestational day (GD) 9 embryos were exposed in vitro for 48 hr to either HAL, RES, or one of two specific blockers of dopamine receptor subtypes. Schering 23390 (SCH) was used as the D1 blocker, and sulpiride (SULP) as the D2 blocker. The in vivo experiment showed that twice-daily exposure to subcutaneous injections of HAL (5 mg/kg for each of the 2 injections) or RES (0.1 mg/kg for each injection) permanently stunted brain growth when injections were given in midpregnancy (GD 12-16), but not in late pregnancy (GD 16-20). RES was substantially more fetotoxic than HAL, especially late in pregnancy. The growth stunting produced by either compound with GD 12-16 exposure was not restricted to dopamine-rich areas of the brain, or indeed to the brain itself, in that body weight was also depressed. Pair-fed controls did not show the same magnitude or duration of stunting, indicating that this effect was not due to drug-induced maternal hypophagia. The in vitro experiment revealed that exposure to micromolar concentrations of any of the 4 neuroleptics reduced embryonic GD 11 DNA and protein content and delayed development. HAL and SCH had the most pronounced effects at concentrations close to blood levels reportedly produced by exposure to doses used in the in vivo experiments. RES was less potent, and SULP still less potent than RES.(ABSTRACT TRUNCATED AT 400 WORDS)
Holson
R R
RR
Division of Reproductive and Developmental Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079.
Webb
P J
PJ
Grafton
T F
TF
Hansen
D K
DK
D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity*; D001552:Benzazepines / Q000633:toxicity; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000002:abnormalities* / Q000187:drug effects; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D005865:Gestational Age; D006128:Growth / Q000187:drug effects*; D006220:Haloperidol / Q000633:toxicity; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D011919:Rats, Inbred Strains; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors; D015203:Reproducibility of Results; D012110:Reserpine / Q000633:toxicity; D012727:Sex Characteristics; D013469:Sulpiride / Q000633:toxicity; D013723:Teratogens / Q000633:toxicity
D014150:Antipsychotic Agents; D001552:Benzazepines; D065127:Dopamine D2 Receptor Antagonists; D017447:Receptors, Dopamine D1; D013723:Teratogens; D013469:Sulpiride; D012110:Reserpine; D006220:Haloperidol