Prolactin Induces IL-2 Associated TRAIL Expression on Natural Killer Cells from Chronic Hepatitis C Patients In vivo and In vitro.

BACKGROUND: Natural killer cells (NKC) are a major component of the innate immune response to HCV, mediating their effects through TRAIL and IFN-γ. However, their function is diminished in chronic HCV patients (HCVp). Prolactin is an immunomodulatory hormone capable of activating NKC. OBJECTIVE: The study aims to explore if hyperprolactinemia can activate NKC in HCVp. METHODS: We treated twelve chronic HCVp (confidence level =95%, power =80%) for 15 days with Levosulpiride plus Cimetidine to induce mild hyperprolactinemia. Before and after treatment, we determined TRAIL and NKG2D expression on peripheral blood NKC, along with cytokine profiles, viral loads and liver function. We also evaluated in vitro effects of prolactin and/or IL-2 on NKC TRAIL or NKG2D expression and IFN-γ levels on cultured blood mononuclear cells from 8 HCVp and 7 healthy controls. RESULTS: The treatment induced mild hyperprolactinemia and increased TRAIL expression on NKC as well as the secretion of IL-1ra, IL-2, PDGF and IFN-γ. Viral loads decreased in six HCVp. IL-2 and TRAIL together explained the viral load decrease. In vitro, prolactin plus IL-2 synergized to increase TRAIL and NKG2D expression on NKC from HCVp but not in controls. CONCLUSION: Levosulpiride/Cimetidine treatment induced mild hyperprolactinaemia that was associated with NKC activation and Th1-type cytokine profile. Also, an increase in TRAIL and IL-2 was associated with viral load decrease. This treatment could potentially be used to reactivate NKC in HCVp.

Acute dopamine receptor blockade in substantia nigra pars reticulata: a possible model for drug-induced Parkinsonism.

Dopamine (DA) depletion modifies the firing pattern of neurons in the substantia nigra pars reticulata (SNr), shifting their mostly tonic firing toward irregularity and bursting, traits of pathological firing underlying rigidity and postural instability in Parkinson's disease (PD) patients and animal models of Parkinsonism (PS). Drug-induced Parkinsonism (DIP) represents 20-40% of clinical cases of PS, becoming a problem for differential diagnosis, and is still not well studied with physiological tools. It may co-occur with tardive dyskinesia. Here we use in vitro slice preparations including the SNr to observe drug-induced pathological firing by using drugs that most likely produce it, DA-receptor antagonists (SCH23390 plus sulpiride), to compare with firing patterns found in DA-depleted tissue. The hypothesis is that SNr firing would be similar under both conditions, a prerequisite to the proposal of a similar preparation to test other DIP-producing drugs. Firing was analyzed with three complementary metrics, showing similarities between DA depletion and acute DA-receptor blockade. Moreover, blockade of either nonselective cationic channels or Cav3 T-type calcium channels hyperpolarized the membrane and abolished bursting and irregular firing, silencing SNr neurons in both conditions. Therefore, currents generating firing in control conditions are in part responsible for pathological firing. Haloperidol, a DIP-producing drug, reproduced DA-receptor antagonist firing modifications. Since acute DA-receptor blockade induces SNr neuron firing similar to that found in the 6-hydroxydopamine model of PS, output basal ganglia neurons may play a role in generating DIP. Therefore, this study opens the way to test other DIP-producing drugs. NEW & NOTEWORTHY Dopamine (DA) depletion enhances substantia nigra pars reticulata (SNr) neuron bursting and irregular firing, hallmarks of Parkinsonism. Several drugs, including antipsychotics, antidepressants, and calcium channel antagonists, among others, produce drug-induced Parkinsonism. Here we show the first comparison between SNr neuron firing after DA depletion vs. firing found after acute blockade of DA receptors. It was found that firing in both conditions is similar, implying that pathological SNr neuron firing is also a physiological correlate of drug-induced Parkinsonism.

The antipsychotics sulpiride induces fatty liver in rats via phosphorylation of insulin receptor substrate-1 at Serine 307-mediated adipose tissue insulin resistance.

Cumulative evidence has suggested that many antipsychotics cause metabolic abnormalities. Adipose tissue insulin resistance (Adipo-IR) contributes to the development and progress of metabolic abnormalities including fatty liver by inducing excessive free fatty acid release from adipose tissue. Sulpiride is an old antipsychotic still frequently used in many developing countries. However, its adverse metabolic effects remain poorly understood. Here, chronic administration of sulpiride (80 mg/kg, subcutaneously, once daily for 6 weeks) elevated fasting insulin concentration and the index of the homeostasis model assessment of insulin resistance in rats. More importantly, sulpiride increased hepatic triglyceride accumulation and Oil Red O-stained area, indicating the induction of fatty liver by sulpiride. Sulpiride also increased plasma non-esterified fatty acid concentrations at the baseline and during an oral glucose tolerance test, the Adipo-IR index, and adipocyte size. Adipose gene expression profile revealed that sulpiride decreased mRNA and protein expression of insulin receptor substrate (IRS)-1, but not IRS-2. Furthermore, sulpiride increased phosphorylation of both Ser307 in IRS-1 and Ser473 in Akt at baseline. Co-treatment with bromocriptine (a dopamine D2 receptor agonist) attenuated sulpiride-induced hyperprolactinemia, but it was without effect on insulin resistance and fatty liver. Therefore, the present results suggest that sulpiride induces fatty liver in rats via phosphorylation of IRS-1 at Ser307-mediated adipose tissue insulin resistance, in which dopamine D2 receptor is possibly not involved. Our findings may provide new insights into the mechanisms underlying the steatotic effect of the old antipsychotic.

[Toxicity assessment of sulpiride as the basis of its hygienic standardization].

Toxic properties of sulpiride were studied with an aim of its hygienic standardization. LD50 of sulpiride in administration into the stomach of male rats and mice is 7200 and 3400 mg/kg, for female rats and mice - 6000 and 2300 mg/kg. It refers to substances of hazard Classes 3, 4. No significant differences were noted in the species and sex sensitivity of animals to a substance. In intraperitoneal administration LD50 for male rats is 220 mg/kg, for female rats--150 mg/kg. It has a pronounced cumulation ability, cumulation coefficient: Kcum equals 2.9. It has not a local irritant effect on the skin. There were no identified skin-resorptive and sensitizing effects. It causes a slight irritant effect on the mucous membranes of the eyes. It has a toxic effect on the central nervous system, liver, kidneys. Threshold of acute inhalation action is--63.5 mg/m3. Occupational safety level of exposure to sulpiride in the working area air is 0.5 mg/m.

Differential stimulation pathways of progesterone secretion from newly formed corpora lutea in rats treated with ethylene glycol monomethyl ether, sulpiride, or atrazine.

Ethylene glycol monomethyl ether (EGME), sulpiride, and atrazine are known ovarian toxicants, which increase progesterone (P4) secretion and induce luteal cell hypertrophy following repeated administration. The aim of this study was to define the pathways by which these compounds exerted their effects on the ovary and hypothalamic-pituitary-gonadal (HPG) axis. In the ovary, changes in the steroidogenic activity of new and old corpora lutea (CL) were addressed. EGME (300 mg/kg), sulpiride (100 mg/kg), or atrazine (300 mg/kg) were orally given daily for four times from proestrus to diestrus in normal cycling rats. Treatment with all chemicals significantly increased serum P4 levels, and EGME as well as sulpiride induced increases in prolactin (PRL) levels. In new CL, at both the gene and the protein levels, all three chemicals upregulated the following steroidogenic factors: scavenger receptor class B type I, steroidogenic acute regulatory protein, P450 cholesterol side-chain cleavage, and 3ß-hydroxysteroid dehydrogenase (HSD) and downregulated the luteolytic gene, 20α-HSD. Coadministration of EGME and bromocriptine, a D2 agonist, completely inhibited PRL but not P4 secretion. Additionally, steroidogenic factor expression levels were upregulated, and 20α-HSD level was downregulated in new CL. These results suggest that EGME both directly and indirectly stimulates P4 production in luteal cells, whereas sulpiride elevates P4 through activation of PRL secretion in the pituitary. Atrazine may directly activate new CL by stimulating steroidogenic factor expressions. The present study suggests that multiple pathways mediate the effects of EGME, sulpiride, and atrazine on the HPG axis and luteal P4 production in female rats in vivo.

Amisulpride-induced seizurogenic effect: a potential role of opioid receptor-linked transduction systems.

This study was designed to investigate the role of opioid receptors, gamma-aminobutyric acid (GABA) receptors, mast cells and histamine receptors (H(1) subtype) in the seizurogenic effect of amisulpride on mice. A single injection of amisulpride (180 mg/kg) was employed to evaluate the seizurogenicity of the drug in mice. Seizures were assessed in terms of a composite seizure severity score (SSS), time of the onset of straub-like tail, onset of jerky movements of whole body, convulsions and death. Amisulpride administration (180 mg/kg) induced a significant pro-convulsant effect in mice as measured in terms of the SSS (21.12 ± 2.71) and a significant decrease in the time latency of the onset of straub-like tail (132.45 ± 12.31), jerky movements of whole body (153.28 ± 14.12), convulsions (184.97 ± 13.11) and death (100%). Moreover, prior administration of naloxone, cetrizine, sodium cromoglycate and gabapentin, respectively, attenuated this seizurogenic activity that amisulpride exerted on mice (p < 0.05). Therefore, it may be suggested that amisulpride exerts a seizurogenic effect on mice possibly via an opioid receptor activation-dependent release of histamine from the mast cells and a simultaneous inhibition of GABA release.

Cellular mechanism of the QT prolongation induced by sulpiride.

In this study, the authors investigated the electrophysiological effect of sulpiride on cardiac repolarization using conventional microelectrode recording techniques in isolated canine Purkinje fibers and a whole-cell patch clamp technique in transiently transfected cells with the hERG, KCNQ1/KCNE1, KCNJ2, and SCN5A cDNA and in rat cardiac myocytes for I(Ca). In studies of action potential duration, 10 microM, 100 microM, 300 microM, and 1 mM sulpiride prolonged action potential duration in a concentration-dependent manner. In studies of cardiac ion channels, sulpiride did not significantly affect I(Na), I(Ca), I(Ks), I(K1), except for I(Kr). Sulpiride dose-dependently decreased the hERG tail current. It is considered that the prolonged action potential duration by sulpiride was mainly the result of inhibition of the hERG channel. The data suggest that the clinical use of sulpiride is reasonable within therapeutic plasma concentrations, but all patients taking this drug should be cautiously monitored for clinical signs of long-QT syndrome and severe arrhythmia.

Collaborative work on evaluation of ovarian toxicity. 17) Two- or four-week repeated-dose studies and fertility study of sulpiride in female rats.

To find the appropriate dosing period to detect ovarian toxicity, sulpiride, a D2 antagonist was orally dosed to female rats at dose levels of 1, 10, and 100 mg/kg/day daily for 2 or 4 weeks in repeated-dose toxicity studies. In addition, sulpiride at the same dose levels was given to female rats daily during the pre-mating period, mating period, and Days 0-7 of gestation to assess its effect on fertility. In ovarian histology in the 2-week study, increases in atretic follicle were seen at 1 mg/kg or more and increases in follicular cysts at 10 mg/kg or more. In the 4-week study, these findings were seen at 1 mg/kg or more, and a decrease in large follicles was seen at 10 mg/kg or more. Increased body weight gain was observed at 10 mg/kg or more in the 2- and 4-week studies. The females in these groups exhibited development of mammary alveolus by sulpiride-induced hyperprolactinemia. In the fertility study, sulpiride-treated females showing persistent diestrus resulted in successful mating, and almost all females got pregnant. However, increased implantation loss was observed at 10 mg/kg or more, which was considered to be caused by the adverse effect of sulpiride on oocyte development. From these results, sulpiride-induced ovarian toxicity was seen at 1 mg/kg or more in the 2- and 4-week repeated-dose toxicity studies, and the observed ovarian changes were considered to be related to adverse effects on female fertility.

[Fatal intoxication with amisulpride and presentation of organ distribution]. / Tödliche Intoxikation mit Amisulprid und Darstellung der Organverteilung.

Amisulpride is a substituted benzamide used as an atypical antipsychotic drug. It antagonizes dopamine D2 and D3 receptor-mediated effects with greater affinity for the limbic system suggesting better neurological tolerance than classical neuroleptics. However, occasionally amisulpride intoxications associated with seizures, comatose conditions and agitation, hyperthermia, tachycardia, prolongation of the QT interval and extrapyramidal features have been described. A 27-year-old female with a medical history of psychosis and amisulpride therapy was found dead at home. By means of high performance liquid chromatography coupled with mass spectrometry (LC/MS) an amisulpride concentration of 13.4 mg/l was found in the peripheral blood. A lower concentration in the brain and an extremely high concentration in bile can be explained by the polarity and hydrophobic character of the substance. After macroscopic and histological exclusion of other causes of death the results of the toxicological analysis were consistent with the assumption of a fatal amisulpride overdose.

Effects of novel antipsychotics, amisulpiride and aripiprazole, on maternal behavior in rats.

RATIONALE: Rat maternal behavior, which entails complex motivational and social factors, is disrupted by the currently available typical and atypical antipsychotics. It is thought that this disruption reflects a side effect of antipsychotics, modeling the neuroleptic-induced negative or deficit state. Amisulpiride and aripiprazole are new atypical antipsychotics with mechanisms of action distinct from the current typical and atypical antipsychotics. The effects of these drugs on maternal behavior have not been explored. OBJECTIVE: In the present study, we systematically examined the behavioral effects of amisulpiride and aripiprazole on maternal behavior in postpartum female rats. METHODS: Various components of maternal behavior (pup retrieval, pup licking, nest building and pup nursing) were examined repeatedly over a period of 24 h after a single injection of three doses of amisulpiride (10, 30, and 100 mg/kg s.c.) and aripiprazole (3, 10, and 30 mg/kg). RESULTS: Amisulpiride at the lower doses (10 and 30 mg/kg) enhanced pup licking, and only at the highest dose disrupted the active components of maternal behavior such as pup retrieval and nest building. Its effect was delayed in onset and prolonged as compared to other antipsychotics. Aripiprazole, even at the highest dose (30 mg/kg) did not impair pup retrieval or pup licking. However, it did disrupt nest building and led to enhanced pup nursing. CONCLUSIONS: The unique effects of these two drugs may be due to their unique actions at the mesolimbic dopamine synapses. The sparing of the major components of maternal behavior by aripiprazole may be related to its partial agonist effects, whereas the enhancement of pup licking by amisulpiride may be related to its dose-dependent preferential effect on the presynaptic autoreceptors. The potential clinical implications of these findings are discussed.

Effect of the amisulpride isomers on rat catalepsy.

The substituted benzamide amisulpride is currently administered in its racemic form. In the present study, the biochemical and cataleptogenic profiles of the two enantiomers (R+ and S-) were compared with those of the racemic mixture. Displacement binding studies showed that the (S-)-isomer possesses an higher affinity for dopamine D2-like receptor (K(i) 5.2+/-0.4 nM) compared to (R+)-amisulpride (K(i) 244+/-12 nM) and to (RS)-amisulpride (K(i) 9.8+/-0.8 nM). In contrast, (S-)-amisulpride binds the alpha(2)-receptor with an affinity (K(i) 1528+/-45 nM) lower than that of the (R+)-isomer (K(i) 375+/-34 nM) and of (RS)-amisulpride (K(i) 783+/-27 nM). The bar test was used to evaluate the catalepsy induced by each drug. (RS)-amisulpride induced catalepsy only at very high doses (>100 mg/kg, s.c.) whereas, (S-)-amisulpride produced a catalepsy at a lower dose (30 mg/kg, s.c.) and (R+)-amisulpride did not produce any catalepsy up to the dose of 75 mg/kg. Interestingly, (R+)-amisulpride reduced the catalepsy induced by (S-)-amisulpride (50 mg/kg, s.c.) or haloperidol (0.3 mg/kg, s.c.), at the doses of 50 or 30 mg/kg, respectively. These results indicate that the weak cataleptic properties of (RS)-amisulpride might partially rely on its (R+)-isomer and provide a further explanation for the atypical properties of amisulpride as an antipsychotic.

Sub-chronic treatment with classical but not atypical antipsychotics produces morphological changes in rat nigro-striatal dopaminergic neurons directly related to "early onset" vacuous chewing.

In the present work, we investigated if an impairment of dopaminergic neurons after subchronic haloperidol treatment might be a possible physiopathologic substrate of the "early onset" vacuous chewing movements (VCMs) in rats. For this purpose, different antipsychotics were used to analyse a possible relationship between VCMs development and morphological alterations of tyrosine-hydroxylase-immunostained (TH-IM) neurons. Rats treated twice a day with haloperidol displayed a significant increase of VCMs that was both time- (2-4 weeks) and dose (0.1-1 mg/kg) dependent. Immunocytochemical analysis showed a shrinkage of TH-IM cell bodies in substantia nigra pars compacta and reticulata and a reduction of TH-immunostaining in the striatum of haloperidol treated rats with the arising of VCMs. No differences were observed in TH-IM neurons of ventral tegmental area and nucleus accumbens vs. control rats. The atypical antipsychotics risperidone (2 mg/kg, twice a day), amisulpride (20 mg/kg, twice a day) and clozapine (10 mg/kg, twice a day) did not produce any nigro-striatal morphological changes or VCMs. TH-IM nigro-striatal neuron morphological alterations and VCMs were still present after three days of withdrawal in rats treated for four weeks with haloperidol (1 mg/kg). Both the main morphological changes and the behavioural correlate disappeared after three weeks of withdrawal. These results suggest that haloperidol induces a morphological impairment of the dopaminergic nigro-striatal neurons which is directly associated with the arising, permanency and disappearance of VCMs in rats.

Potentiation of ethanol-induced loss of the righting reflex by ascorbic acid in mice: interaction with dopamine antagonists.

The present investigation was carried out to determine the effect of ascorbic acid on ethanol-induced loss of the righting reflex (LORR) and the interactions between ascorbic acid and dopamine receptor antagonists in affecting this action of ethanol in mice. To test the effect of each drug on ethanol-induced LORR, ascorbic acid (31.25, 62.5, 125, 250, 500, 1000 mg/kg intraperitoneally [IP]) and dopamine receptor antagonists (haloperidol 0.5, 1.0 mg/kg; L-sulpiride 20, 40, 80 mg/kg; clozapine 0.625, 1.25, 2.5 mg/kg; SCH 23390 0.5, 1.0, 2.0 mg/kg subcutaneously [SC]) were administered, respectively, 30 min before ethanol (4.0 g/kg IP) administration. Ascorbic acid, at the dose of 1000 mg/kg, significantly potentiated ethanol-induced LORR in mice. Dopamine D(2) antagonists haloperidol (0.5, 1.0 mg/kg SC), and L-sulpiride (80 mg/kg SC) also significantly prolonged the duration of LORR induced by ethanol. Clozapine and SCH 23390, at the doses used, did not affect ethanol-induced LORR. In the interaction study, the synergistic effect of ascorbic acid (1000 mg/kg IP) on ethanol-induced LORR was significantly enhanced by dopamine D(2) antagonists haloperidol, L-sulpiride, and clozapine, and the highest dose of dopamine D(1) antagonist SCH 23390. These results suggest that ascorbic acid may potentiate ethanol-induced LORR partially via a mechanism mainly linked to blockade of dopamine D(2) receptors.

Nicotine potentiates sulpiride-induced catalepsy in mice.

The effects of nicotine on sulpiride-induced catalepsy in mice were investigated. Sulpiride (12.5-100 mg/kg) induced a low degree of catalepsy in mice which was dose dependent. Nicotine (0.0001-1 mg/kg) caused an even lower degree of catalepsy. When the drugs were co-administered a much higher cataleptogenic response was obtained. The potentiation of the effect of sulpiride by nicotine was elicited by 0.5 mg/kg or higher doses of the drug. The central nicotinic receptor antagonist mecamylamine (1-3 mg/kg) and the peripheral antagonist hexamethonium (5 and 10 mg/kg) decreased the response induced by the combination of nicotine and sulpiride. Higher doses of the cholinoceptor antagonist atropine (10 mg/kg) also reduced the catalepsy induced by the drug combination. It is concluded that nicotine potentiates sulpiride-induced catalepsy through activation of cholinergic mechanism(s) and that the central nicotinic mechanism mediates nicotine's action.

The behavioural effects of pramipexole, a novel dopamine receptor agonist.

Pramipexole (SND 919; 2-amino-4,5,6,7-tetrahydro-6-propyl-amino-benzthiazole-dihydroc hlo ride) is a novel dopamine D2 family receptor agonist with a predominant action on D2 autoreceptors and with some D3 vs. D2 receptor preference. The central behavioural effects of pramipexole given subcutaneously to rats (male Wistar) and mice (Albino Swiss) are presented in this paper. Used in low doses (0.001-0.1 mg/kg), pramipexole induced locomotor hypoactivity which was antagonized by a low dose of spiperone; at higher doses (0.3, 1 mg/kg) it evoked hyperactivity which was inhibited by haloperidol, sulpiride and clozapine, but not by SCH 23390 (R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine hydrochloride). Pramipexole (0.1-1.0 mg/kg) antagonized the akinesia induced by combined pretreatment with reserpine (5 mg/kg) and alpha-methyl-p-tyrosine (250 mg/kg). Pramipexole (0.1-1 mg/kg) potentiated the hyperkinetic effect of L-DOPA (L-3,4-dihydroxyphenylalanine) (50 and 200 mg/kg, together with benserazide, 50 mg/kg) in naive and monoamine-depleted (reserpine + alpha-methyl-p-tyrosine) rats. The higher doses of pramipexole (1 and 3 mg/kg) evoked stereotypy which was antagonized by pretreatment with sulpiride or clozapine. The catalepsy induced by haloperidol, spiperone or fluphenazine was antagonized by pramipexole (1-3 mg/kg). Pramipexole (1 mg/kg) induced hypothermia in mice, which was antagonized by sulpiride. The obtained results indicate that pramipexole: (i) at low doses stimulates the dopamine D2 presynaptic autoreceptors; (ii) at higher doses stimulates dopamine D2 postsynaptic receptors. An effect on the dopamine D3 receptor cannot be excluded. At low doses pramipexole may have antipsychotic activity, and at higher ones antiparkinsonian activity.

BMY-14802 reversed the sigma receptor agonist-induced neck dystonia in rats.

To clarify clinical roles of sigma receptor binding affinity of neuroleptics, neck dystonia induced by microinjection of sigma receptor ligands and neuroleptics into rat red nucleus was investigated. DTG and (+)-3-PPP, putative sigma receptor agonists, induced neck dystonia in dose-dependent and reversible manner. Haloperidol and perphenazine induced dystonia in the same way as sigma receptor agonists, whereas zotepine and (-)-sulpiride did not. The rank order of potency in induction of dystonia and sigma receptor affinity of these compounds showed positive correlation. Although BMY-14802 has a high affinity for sigma receptors, it never produced dystonia by itself. On the other hand, combined injection of BMY-14802 with DTG attenuated DTG-induced dystonia. Therefore, it is suggested that typical neuroleptics such as haloperidol act agonistic and atypical neuroleptics such as BMY-14802 act antagonistic at rubral sigma receptors in the induction of neck dystonia.

Pharmacotoxicological aspects of levosulpiride.

Levosulpiride is the levorotatory enantiomer of sulpiride, a substituted benzamide indicated as an antipsychotic, antidepressant, antiemetic and antidyspeptic drug, as well as for the treatment of somatoform disorders. In vivo sulpiride displays a number of neuroleptic properties which it shares with all typical neuroleptic drugs; however, it has also a number of divergent characteristics that set it apart as the principal compound of the so-called 'atypical neuroleptic agents'. The main mechanism of action of levosulpiride consists of blocking the D2 dopaminergic receptors, preferentially located on the presynaptic membranes in the dopaminergic pathways of the brain; this means that sulpiride is a selective autoreceptor blocker. The results of series of experimental trials conducted to evaluate the toxicologic characteristics of levosulpiride are presented. Both the acute, subacute, chronic and local toxicity trials, and the studies on reproduction toxicity, mutagenic potential and oncogenic/carcinogenic potential, demonstrate that levosulpiride is well tolerated by the animals tested (rats, mice, rabbits and dogs) at doses higher than those effective in human therapy. Moreover, the findings from the experimental studies on levosulpiride lead to exclude the toxicity from accumulation, tolerance, dependence or withdrawal syndrome. In conclusion, according to the evaluated preclinical studies, levosulpiride shows pharmacotoxicologic properties which make it suitable for the management of diseases for which the drug is indicated.

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)