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 pl ay a trophic role in the development of the central nervous system. Do pamine is one candidate for this role. In a series of papers, Lewis, P atel, and colleagues have demonstrated that exposure to compounds whic h 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 e xposure to haloperidol (HAL), a neuroleptic which binds to and blocks dopamine receptor sites in the adult brain, permanently stunts body an d 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 reserpi ne (RES), a compound which in the adult blocks dopaminergic neurotrans mission by rupturing monoamine storage vesicles, an effect which is qu ite distinct from the HAL mechanism of action. In a second experiment, gestational day (GD) 9 embryos were exposed in vitro for 48 hr to eit her HAL, RES, or one of two specific blockers of dopamine receptor sub types. Schering 23390 (SCH) was used as the D1 blocker, and sulpiride (SULP) as the D2 blocker. The in vivo experiment showed that twice-dai ly exposure to subcutaneous injections of HAL (5 mg/kg for each of the 2 injections) or RES (0.1 mg/kg for each injec tion) permanently stun ted brain growth when injections were given in midpregnancy (GD 12-16) , but not in late pregnancy (GD 16-20). RES was substantially more fet otoxic than HAL, especially late in pregnancy. The growth stunting pro duced 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 th at body weight was also depressed. Pair-fed controls did not show the same magnitude or duration of stunting, indicating that this effect wa s not due to drug-induced maternal hypophagia. The in vitro experiment revealed that exposure to micromolar concentrations of any of the 4 n euroleptics reduced embryonic GD 11 DNA and protein content and delaye d development. HAL and SCH had the most pronounced effects at concentr ations close to blood levels reportedly produced by exposure to doses used in the in vivo experiments. RES was less potent, and SULP still l ess potent than RES. It is concluded that neuroleptics acting through a variety of mechanisms can permanently stunt growth. There is a sensi tive period for this stunting in midgestation. These effects are proba bly the result of direct drug action on the fetus, at least in the cas e of HAL, in that direct embryonic exposure to HAL in vitro at levels similar to those probably attained in vivo likewise slowed growth and development. Furthermore, the HAL effect on growth may be due in part to a direct effect on a D1-like receptor, in that equimolar exposure t o SCH had a very similar depressive effect on embryonic growth and dif ferentiation. (C) 1994 Wiley-Liss, Inc.