PMID- 7801300 OWN - NLM STAT- MEDLINE DCOM- 19950125 LR - 20141120 IS - 0040-3709 (Print) IS - 0040-3709 (Linking) VI - 50 IP - 2 DP - 1994 Aug TI - Prenatal neuroleptic exposure and growth stunting in the rat: an in vivo and in vitro examination of sensitive periods and possible mechanisms. PG - 125-36 AB - 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) FAU - Holson, R R AU - Holson RR AD - Division of Reproductive and Developmental Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079. FAU - Webb, P J AU - Webb PJ FAU - Grafton, T F AU - Grafton TF FAU - Hansen, D K AU - Hansen DK LA - eng PT - Comparative Study PT - Journal Article PL - United States TA - Teratology JT - Teratology JID - 0153257 RN - 0 (Antipsychotic Agents) RN - 0 (Benzazepines) RN - 0 (Dopamine D2 Receptor Antagonists) RN - 0 (Receptors, Dopamine D1) RN - 0 (Teratogens) RN - 7MNE9M8287 (Sulpiride) RN - 8B1QWR724A (Reserpine) RN - J6292F8L3D (Haloperidol) SB - IM MH - Analysis of Variance MH - Animals MH - Antipsychotic Agents/*toxicity MH - Benzazepines/toxicity MH - Body Weight/drug effects MH - Brain/*abnormalities/drug effects MH - Dopamine D2 Receptor Antagonists MH - Dose-Response Relationship, Drug MH - Embryonic and Fetal Development/drug effects MH - Feeding Behavior/drug effects MH - Female MH - Gestational Age MH - Growth/*drug effects MH - Haloperidol/toxicity MH - Male MH - Organ Size/drug effects MH - Pregnancy MH - *Prenatal Exposure Delayed Effects MH - Rats MH - Rats, Inbred Strains MH - Receptors, Dopamine D1/antagonists & inhibitors MH - Reproducibility of Results MH - Reserpine/toxicity MH - Sex Characteristics MH - Sulpiride/toxicity MH - Teratogens/toxicity EDAT- 1994/08/01 00:00 MHDA- 1994/08/01 00:01 CRDT- 1994/08/01 00:00 PHST- 1994/08/01 00:00 [pubmed] PHST- 1994/08/01 00:01 [medline] PHST- 1994/08/01 00:00 [entrez] AID - 10.1002/tera.1420500207 [doi] PST - ppublish SO - Teratology. 1994 Aug;50(2):125-36. doi: 10.1002/tera.1420500207.