Failure of chronic haloperidol to affect prolactin secretion due to acute haloperidol administration

Withdrawal from chronic haloperidol exposure was associated to unaltered circulating levels of prolactin (PRL), decreased 3H-spiperone binding sites in the anterior pituitary and increased 3H-spiperone binding sites in the striatum of male rats. Haloperidol (0.1 mg/kg ip) induced similar rises in plasma PRL in haloperidol-or saline-treated rats and the dose of 0.01 mg/kg was ineffective in both groups. These findings illustrate the poor relatedness existing at the pituitary D2 receptor between biochemical and functional indices.     

GM1 ganglioside attenuates the development of vacuous chewing movements induced by long-term haloperidol treatment of rats

Tardive dyskinesia (TD) is a serious side-effect of long-term treatment with neuroleptics. To investigate if TD may be a result of neuroleptic-induced excessive stimulation of striatal glutamate receptors, the effect of the anti-excitotoxic GM1 ganglioside was studied in a rat model of TD. In an acute experiment each of four groups of rats was treated with GM1 20 mg/kg SC + saline IP, saline SC + haloperidol 1.2 mg/kg IP, GM1 SC + haloperidol IP, or saline SC + saline IP. In a subsequent long-term experiment lasting 16 weeks, each of the four groups was treated as in the acute experiment, with the exception that haloperidol was injected IM as decanoate 38 mg/kg every 4 weeks, and the controls received vehicle injections. The behaviour was videotaped and scored at intervals during both experiments, including 16 weeks after cessation of the long-term treatment. Haloperidol induced a significant increase in vacuous chewing movements (VCM) and immobility both in the acute and in the long-term experiment. Other categories of behaviour (rearing, moving, sitting) were significantly affected only in the acute experiment. GM1 did not affect any of the acute behavioural effects of haloperidol, but significantly reduced VCM in the long-term experiment. The effects on VCM of haloperidol and GM1 persisted for at least 8 weeks after cessation of the long-term treatment. These results suggest that long-lasting changes in striatal function induced by excessive glutamate receptor stimulation may be a mechanism for the development of VCM in rats and perhaps also for TD in humans.     

Effects of acute and chronic haloperidol treatment on the concentrations of immunoreactive beta-endorphin in plasma, pituitary and brain of rats

Haloperidol (0.03-3 mg/kg) dose-dependently increased the plasma concentrations of immunoreactive beta-endorphin (ir-beta-END) without changing the concentrations of ir-beta-END in the adenohypophysis or the neurointermediate pituitary of rats. Elevated levels of ir-beta-END in plasma were also found after chronic treatment with haloperidol (1 mg/kg per day) for 3 weeks. The long-term treatment, however, caused a selective increase (60%) of the ir-beta-END concentrations in the neurointermediate pituitary without changing that in the adenohypophysis. Significantly elevated levels of ir-beta-END were also found in the hypothalamus and the septum. Gelchromatographic separation of the plasma components reacting with the beta-endorphin antiserum revealed that both the acute and chronic haloperidol treatment increased the plasma concentrations of immunoreactive material with the molecular size of beta-endorphin and beta-lipotropin. This indicates that, at least, part of ir-beta-END released by haloperidol into plasma is of adenohypophyseal origin, since no material with the molecular size of beta-lipotropin has been found in the neurointermediate pituitary.     

Subtle behavioural changes produced in rat pups by in utero exposure to haloperidol

Prenatal exposure to a dopamine receptor blocking agent such as haloperidol (given to the mother at a dose of 0.5 mg/kg s.c. from day 4 to day 15 of gestation) produced subtle behavioural changes in rat pups. Haloperidol decreased the rate of ultrasonic vocalization in 4-day-old male pups removed from the nest. The changes in ultrasonic emission elicited by in utero exposure to this neuroleptic were markedly different from those produced by its administration during the early postnatal period. Moreover, adult male rats treated prenatally with haloperidol exhibited a significant increase in the intensity of ultrasonic 22 kHz post-ejaculatory calls emitted during sexual behaviour. The duration of the period of the 22 kHz calls emission was also significantly increased by haloperidol treatment. These results confirm that ultrasonic vocalization in rats is a sensitive indicator of subtle changes in adverse treatments administered during development.     

Chronic haloperidol treatment with low doses may enhance the increase of homovanillic acid in rat brain

Homovanillic acid (HVA) levels were determined by high performance liquid chromatography with electrochemical detection in the striatum and prefrontal cortex of rats that had received single or repeated injections of various doses of haloperidol. Haloperidol increased the HVA concentrations in both brain regions after both acute and chronic treatment with doses of 0.01-1 mg/kg. The increase in the HVA concentrations in the striatum was blunted after repeated haloperidol injections with doses of 0.5-1 mg/kg, suggesting that haloperidol pretreatment results in a decreased responsiveness to the drug at high doses (tolerance). Tolerance also developed to the effect of long-term haloperidol treatment on the HVA concentrations in the prefrontal cortex at the highest dose used (1 mg/kg). This suggests that the differences in the development of tolerance between the striatum and prefrontal cortex are not qualitative but quantitative. However, repeated haloperidol injections at doses of 0.01-0.05 mg/kg enhanced the increase in HVA concentrations. This suggests that tolerance does not develop after chronic haloperidol treatment with low doses. Decreased HVA concentrations were also found after withdrawal from chronic haloperidol treatment (rebound decrease). However, this rebound decrease was much smaller than the decrease in response of the HVA concentrations to repeated haloperidol injections, suggesting that different mechanisms are involved.     

Tolerance of haloperidol catalepsy

Haloperidol (0.75 and 1.5 mg/kg p.o.) was administered daily for 16 days to male Wistar rats. The animals received an acute injection of haloperidol (0.5-2.0 mg/kg i.p. or 1.0-4.0 mg/kg p.o.) and catalepsy was measured. After 16 days on haloperidol, all animals became tolerant to the drug, exhibiting decreased cataleptic response to haloperidol; the intensity of catalepsy returned to normal after an additional 16 days abstinence from the drug. In addition, a group of animals treated and tested daily for catalepsy demonstrated that the time course of tolerance development to haloperidol was biphasic, with a rapid phase (T1/2 = 2.5 days) and a slower phase (T1/2 = 5.5 days).     

Prolactin-releasing effect of zetidoline, a new neuroleptic agent, in the rat

The effect of a new neuroleptic agent, zetidoline, 1-(3-chlorophenyl)-3-[2-(3,3-dimethyl-l-azetidinyl)ethyl]imidaz olidin-2-one (ZET), on prolactin release was studied in both male and female rats and compared to that of the classic antipsychotic drugs chlorpromazine and haloperidol. Time-course and dose-effect studies showed that ZET induces a rapid and short lasting increase in plasma prolactin levels, with a significant increase after a dose as low as 0.33 mg/kg, i.p.. The overall patterns of prolactin release appeared to be similar in both sexes but the response was markedly greater in females than in males. The prolactin-releasing effect of ZET was counteracted by apomorphine and L-dopa, which indicates that blockade of dopamine receptors is the basis of its neuroendocrine action. As a prolactin-releaser, ZET was found to be about 5 times as potent as chlorpromazine and about one-ninth as potent as haloperidol.     

Relation between dopaminergic control of pituitary lactotroph function and deceleration of age-related changes in serum prolactin of diet-restricted rats

Pituitary lactotroph function has been examined in diet-restricted (6 hr/day) male and female rats and compared with that in animals fed ad lib. After 12 months the age-related increase in serum prolactin concentration was significantly attenuated in diet-restricted female rats. Similar effects were not observed in male rats. Isolated superfused anterior pituitary glands removed from rats on both feeding regimens at 12 or 18 months and challenged with dopamine in vitro (5 microM) did not show differential prolactin secretion. No significant differences were observed in serum prolactin secretion in vivo after administration of bromocriptine (3 mg/kg body weight, sc) or haloperidol (1.75 mg/kg body weight, ip). These results do not support an altered dopamine receptor function in the anterior pituitary lactotrophs. In contrast, central dopamine receptor function in rats 12 months of age was altered by dietary restriction, since the frequency of cataleptic responses to haloperidol injection (2 mg/kg body weight, ip) was significantly depressed in the test animals.     

Partial agonist properties of the antipsychotics SSR181507, aripiprazole and bifeprunox at dopamine D2 receptors: G protein activation and prolactin release

Dopamine D2 receptor antagonists induce hyperprolactinemia depending on the extent of D2 receptor blockade. We compared the effects of the new antipsychotic agents SSR181507 ((3-exo)-8-benzoyl-N-[[(2 s)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride), bifeprunox (DU127090: 1-(2-Oxo-benzoxazolin-7-yl)-4-(3-biphenyl)methylpiperazinemesylate) and SLV313 (1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluorophenyl)-pyridin-3-ylmethyl]-piperazine) with those of aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butyloxy)-3,4-dihydro-2(1 H)-quinolinone), clozapine and haloperidol, on functional measures of dopamine D2 receptor activity in vitro and in vivo: [35S]-GTPgammaS binding to membranes from Sf9 insect cells expressing human dopamine D2 Long (hD2 L) receptors, and serum prolactin levels in the rat. All compounds antagonized apomorphine-induced G protein activation at dopamine hD2 L receptors. Antagonist potencies of aripiprazole, bifeprunox and SLV313 were similar to haloperidol (pK(b) = 9.12), whereas SSR181507 (8.16) and clozapine (7.35) were less potent. Haloperidol, SLV313 and clozapine were silent antagonists but SSR181507, bifeprunox and aripiprazole stimulated [35S]-GTPgammaS binding by 17.5%, 26.3% and 25.6%, respectively, relative to 100 microM apomorphine (Emax = 100%). pEC50s were: SSR181507, 8.08; bifeprunox, 8.97; aripiprazole, 8.56. These effects were antagonized by raclopride. Following oral administration in vivo, the drugs increased prolactin release to different extents. SLV313 and haloperidol potently (ED50 0.12 and 0.22 mg/kg p.o., respectively) stimulated prolactin release up to 86 and 83 ng/ml. Aripiprazole potently (ED50 0.66 mg/kg p.o.) but partially (32 ng/ml) induced prolactin release. SSR181507 (ED50 4.9 mg/kg p.o.) also partially (23 ng/ml) enhanced prolactin release. Bifeprunox only weakly increased prolactin at high doses (13 ng/ml at 40 mg/kg) and clozapine only affected prolactin at the highest dose tested (41 ng/ml at 40 mg/kg). Prolactin levels of the corresponding vehicle-treated animals were <4.3 ng/ml. These data show that (1) SSR181507, aripiprazole and bifeprunox, but not SLV313, are partial agonists at dopamine hD2 L receptors in vitro; (2) SSR181507, bifeprunox and aripiprazole exhibit reduced prolactin release in vivo compared with drugs that are neutral antagonists at dopamine D2 receptors.     

Influence of long-lasting administration of neuroleptics on cortical NMDA receptors and phencyclidine-induced deficit in the sensorimotor gating in rats.

The aim of this study was to examine the role of cortical NMDA receptors in the antipsychotic action of neuroleptics. Haloperidol (1 mg/kg/day) and clozapine (30 mg/kg/day) were administered to rats in drinking water. Autoradiographic and saturation binding analyses showed that a 3-month treatment with both haloperidol and clozapine increased the density of NMDA receptors labelled with [3H]CGP 39653 (a competitive antagonist) in the parietal and insular cortices. Haloperidol additionally increased the binding of that ligand in the frontal cortex. None of those neuroleptics influenced the binding of [3H]MK-801, an uncompetitive antagonist of NMDA receptors, in the frontal, parietal or insular cortices. A 6-week and a 3-month treatment with haloperidol antagonized the deficit of prepulse inhibition induced by phencyclidine (5 mg/kg s.c.). In contrast, short-term (4-day) administration of that neuroleptic was ineffective. The present study suggests that the increased density of cortical NMDA receptors, induced by long-term neuroleptic administration, may overcome the deficit of sensorimotor gating induced by phencyclidine. However, contribution of such an effect to the antipsychotic activity needs to be established.     

Haloperidol regulates the phosphorylation level of the MEK-ERK-p90RSK signal pathway via protein phosphatase 2A in the rat frontal cortex

Haloperidol, a classical antipsychotic drug, affects the extracellular signal-regulated kinase (ERK) pathway in the brain. However, findings are inconsistent and the mechanism by which haloperidol regulates ERK is poorly understood. Therefore, we examined the ERK pathway and the related protein phosphatase 2A (PP2A) in detail after haloperidol administration. Haloperidol (0.5 and 1 mg/kg) induced biphasic changes in the phosphorylation level of mitogen-activated protein kinase kinase (MEK), ERK, and p90 ribosomal S6 kinase (p90RSK) without changing Raf-1 phosphorylation. Fifteen minutes after haloperidol administration, MEK-ERK-p90RSK phosphorylation increased, whilst PP2A activity decreased. At 60 min, the reverse was observed and the binding of PP2A to MEK and ERK increased. Higher dosages of haloperidol (2 and 4 mg/kg), affected neither MEK-ERK-p90RSK phosphorylation nor PP2A activity. Accordingly, PP2A regulates acute dose- and time-dependent changes in MEK-ERK-p90RSK phosphorylation after haloperidol treatment. These findings suggest the involvement of a dephosphorylating mechanism in the acute action of haloperidol.     

The involvement of sigma and phencyclidine receptors in the action of antipsychotic drugs.

An atypical antipsychotic drug clozapine and a selective sigma antagonist BMY 14802 were significantly less effective in the behavioural experiments (against apomorphine, d-amphetamine and MK-801), as well in the radioligand binding studies against 3H-spiperone (dopamine2-receptors) and 3H-haloperidol (sigma receptors) in the rat brain, as compared to a typical antipsychotic compound haloperidol. Contrary to haloperidol and BMY 14802, clozapine was a relatively selective antagonist of MK-801-induced motor excitation in the mouse. A nearly 3-fold lower dose of clozapine was needed to block the effect of MK-801 (6.4 mumol/kg) as compared to the action of amphetamine (17 mumol/kg). Haloperidol and clozapine, but not BMY 14802, antagonized apomorphine-induced aggressiveness in the rat. After long-term treatment (for 15 days) with BMY 14802 (10 mg/kg daily), haloperidol (0.5 mg/kg daily) and clozapine (10 mg/kg daily) the motor depressant effect of apomorphine (0.15 mg/kg) was reversed. Chronic haloperidol treatment, but not administration of BMY 14802 and clozapine, increased the number of dopamine2-receptors in the rat brain. BMY 14802 caused upregulation of sigma receptors in frontal cortex, whereas haloperidol induced the opposite change in cerebellum. Repeated treatment with clozapine significantly augmented the motor stimulating effect of MK-801 in rats. Simultaneously with a behavioural change the density of 3H-TCP binding sites in the rat forebrain was elevated after long-term treatment with clozapine, probably indicating the involvement of PCP binding sites at NMDA channel in the action of clozapine.     

Alterations in the thermic response to chlorpromazine in rats exposed prenatally to central nervous system depressants

The thermic response to acute administration of chlorpromazine (5 mg/kg, i.p.) was assessed in rats exposed prenatally to haloperidol (0.1 mg/kg), phenobarbital (10 mg/kg), nitrazepam (2 mg/kg), propylene glycol (1 ml/kg) or saline, once daily from days 1-21 or 15-21 of gestation. The response in all animals was tested only once. The administration of chlorpromazine to 8- or 13-week-old male and female rats treated with saline (1-21 d) induced marked hypothermia for a 6-hr period of observation. Male and female rats treated with haloperidol (1-21 d) showed a delayed hyperthermic response to chlorpromazine at 8 weeks of age; the males showed an increase in rectal temperature at 3 hr and the females from 3 to 6 hr. Thirteen-week-old males but not females treated with haloperidol (1-21 d) showed a hyperthermic response to chlorpromazine during the first 2 hr. Eight-week-old male and female rats treated with phenobarbital (1-21 d) showed hypothermia, whereas 13-week-old male rats of another group treated with phenobarbital (1-21 d) showed significant hyperthermia after the administration of the chlorpromazine. The hypothermic response of the rats treated with nitrazepam (1-21 d) to chlorpromazine was similar to that in the vehicle (propylene glycol)-treated controls. The male rats treated with phenobarbital (15-21 d) responded to chlorpromazine with significant hyperthermia from 30 min to 1 hr. There was no alteration in thermic response to chlorpromazine in rats born to mothers treated with one tenth of the dose of phenobarbital, haloperidol or nitrazepam.(ABSTRACT TRUNCATED AT 250 WORDS)     

The antipsychotics haloperidol and chlorpromazine increase bone metabolism and induce osteopenia in female rats

The main objective of this study was to evaluate the effects of the antipsychotic drugs haloperidol (HAL) and chlorpromazine (CPZ) on bone mineral density (BMD) in female rats and to examine the relationship between the effects on bone and reproductive organs or hormone concentrations. Female rats were orally administered HAL (2 or 10 mg/kg) or CPZ (25 or 50 mg/kg) once daily (7 days/week) for 6 months resulting in a significant increase in prolactin. Hyperprolactinemia resulted in enlarged corpora lutea in the ovary, because prolactin has a luteotropic activity. Thus, atrophy in the uterus, epithelial mucification in the vagina and continuous diestrus stages were observed. These events in the reproductive organs induced a decrease in estradiol, elevation of biochemical markers of bone metabolism, significant reductions of BMD in trabecular bone of the femur and decreased trabecular bone in the femur. The bone loss is associated with an increase in bone resorption due to decreased estradiol derived from the luteotropic activity of prolactin. The mechanism of dopamine blockers to induce bone loss in female rats is considered to be rodent specific because the luteotropic effects of prolactin are confined primarily to rodents. Also, it appears that chronic hyperprolactinemia and maintained corpora lutea leading to bone loss are commonly inducible in female rats receiving long-term treatment with antipsychotic drugs possessing dopamine D2 receptor antagonist activity.     

Baclofen, a GABA derivative, inhibits stress-induced prolactin release in the rat

The effect of baclofen, beta-(4-chlorophenyl)GABA, on prolactin secretion was investigated in rats under several experimental conditions. In adult male rats subjected either to immuobilization, ether, swimming or cold stress there was a rapid increase of serum prolactin levels; acute pretreatment with baclofen, 10 mg/kg i.p. inhibited the hormone response to all these stresses. The same blocking effect of the drug was observed in prepubertal male and female rats and in adult gonadectomized animals. In basal conditions, i.e. in undisturbed male rats, baclofen did not change the hormone titers significantly. Taken together our results indicate that baclofen blocks prolactin release when release of the hormone is dynamically stimulated by stress and this effect is relatively independent of the endocrine status of the rat.     

Meal patterns of free feeding rats treated with clozapine, olanzapine, or haloperidol.

Selective dopamine D(2) antogonists increase meal size and decrease the rate of feeding within a meal. Three experiments investigated the extent to which the atypical antipsychotics, clozapine and olanzapine, and the prototypical antipsychotic, haloperidol, affected meal size and feeding rate. Microstructural analyses of meal patterning were made over a range of drug doses administered to free feeding male Lister hooded rats. Haloperidol and clozapine produced a short-term increase in food intake. Haloperidol (0.05-0.2 mg/kg) enhanced meal size (maximal at 0.1 mg/kg) and reduced feeding rate (monotonic decrease with increasing dose). Neither clozapine (1-10 mg/kg) nor olanzapine (0.3-3 mg/kg) enhanced meal size, although both drugs produced similar reductions in feeding rate to haloperidol. These data suggest that enhancement of meal size may be correlated with a high level of extrapyramidal side effects in an antipsychotic drug. The absence of an increase in meal size by two atypical compounds suggests that the increase in body weight associated with clinical treatment with these drugs cannot be modelled by acute stimulation of meal size in the rat.     

Decrease in the evoked release of endogenous dopamine and dihydroxyphenylacetic acid from rat striatal slices after withdrawal from repeated haloperidol

The release of endogenous DA (dopamine) and DOPAC (3,4-dihydroxyphenylacetic acid) from rat striatal slices was measured after withdrawal from a prior long-term treatment of the rat with haloperidol to investigate adaptive changes in striatal DA and DOPAC release induced by chronic haloperidol treatment. Striatal slices prepared 24 h after the last injection of daily treatment with haloperidol for up to 14 days (2.5 mg/kg per day) were superfused and stimulated for 5 min with K+ (50 mM). Haloperidol treatment for 3 or 7 days decreased K(+)-stimulated DA release by maximally 35%, but a 14-day treatment was not effective. The K(+)-stimulated release of DOPAC, which occurred after the change in DA release, was reduced significantly by the treatment for 7 or 14 days. A higher daily dose of haloperidol (10 mg/kg per day) produced a more pronounced decrease in stimulated DA release after a 14-day treatment without having an effect after 3 days. However, the stimulated release of DOPAC decreased markedly after both 3 and 14 days of haloperidol treatment. The slight reduction in the DA content of the slices after K+ stimulation was seen in some haloperidol-treated tissues, although this change did not always parallel the simultaneous decrease in DA release. These results indicate that the K(+)-induced stimulation of endogenous DA release and the synthesis of DA are impaired after withdrawal from repeated haloperidol treatment.     

Unusual interactions between the neuroleptic haloperidol, and the dopamine D2 partial agonist, terguride

Terguride is an ergoline derivative which has been reported to act as a partial agonist at central dopamine D2 receptors. Depending on the state of the receptor, terguride may resemble an agonist or an antagonist in its pharmacological effects. The present study investigated interactions of terguride with the dopamine D2 antagonist haloperidol in the rat. Terguride (0.025 mg/kg, i.p.) lowered, whereas haloperidol (0.025 mg/kg, s.c.) increased serum prolactin levels. When given together there was a tendency for prolactin to be lowered, i.e. terguride fully antagonized the action of haloperidol. Both terguride and haloperidol dose-dependently reduced locomotor activity, with terguride being at least 50 times more potent. However, in the presence of a subthreshold dose of haloperidol (0.1 mg/kg), terguride was effective in reducing locomotor activity. Terguride and haloperidol were equally potent in disrupting performance of lever pressing for food on a VI 120 sec schedule (ED(50) values 0.22 and 0.28 mg/kg, respectively). When given together, there was a statistically significant interaction; a terguride dose of 0.2 mg/kg lowered rates of lever pressing when given with vehicle or a low (0.03 mg/kg) haloperidol dose, but antagonized the effect of 0.3 mg/kg haloperidol. Terguride dose-dependently disrupted lever pressing for intracranial stimulation reward (ED(50) value approx. 0.3 mg/kg). Haloperidol (0.26 mg/kg) also disrupted lever pressing but the two drugs together showed no greater effect than haloperidol alone. These observations are discussed in the context of terguride's suggested partial agonistic properties.     

Adrenal catecholamine concentration after chronic treatment with bromocriptine and haloperidol

Adrenal catecholamine concentration was measured by HPLC with electrochemical detection in male rats after ten days of bromocriptine and haloperidol (0.05,0.5 and 5.0 mg kg^?1) and vehicle (1.0 ml kg^?1) treatments subcutaneously. There were four rats in each group. The results indicate that bromocriptine treatment significantly increased dopamine (DA), noradrenaline (NA) and adrenaline (A) content in a dose-dependent manner. The NA/DA ratio was unchanged, but the A/NA ratio was significantly increased after treatments with two higher doses of the drug. Haloperidol treatment, on the other hand, had no significant effect on dopamine and a biphasic effect on adrenaline content. Noradrenaline concentration increased only after the lowest dose of the drug. There was no significant change in NA/DA or A/NA ratios in any group. The dopamine metabolite, dihydroxyphenylacetic acid (DOPAC), was not detected in any adrenal gland.     

Decrease of prolactin secretion via stimulation of pituitary dopamine D-2 receptors after application of talipexole and SND 919

The present experiments were performed to investigate the effects of talipexole (B-HT 920) and SND 919 on prolactin release from the anterior pituitary glands of rats both in vivo and in vitro. The basal serum prolactin levels were reduced dose dependently by s.c. administration of talipexole or SND 919 at doses of 5-100 micrograms/kg. Daily treatment with estradiol (35 micrograms/kg for 3 days) increased serum prolactin levels in male rats to levels 4-fold higher than those of non-primed rats. This increase was suppressed by administration of talipexole or SND 919. In vitro, the spontaneous prolactin release into perfusates from isolated anterior pituitary was inhibited by talipexole or SND 919 added at concentrations ranging from 10(-9) to 10(-6) M. This inhibitory effect of SND 919 was blocked by concurrent application of a dopamine D-2 receptor antagonist, YM-09151-2. The spontaneous prolactin release from the anterior pituitary isolated from estradiol-primed rats was 2-fold higher than that from non-primed rats. This increased release was also inhibited by application of either drug. The inhibitory effects of these drugs were greater in estradiol-primed rats than in non-primed rats when expressed as percent inhibition of control prolactin release. The results suggest that talipexole and SND 919 have a selective dopamine D-2 receptor agonistic property and are almost completely effective to counteract the enhancement of prolactin release induced by estrogens via stimulation of dopamine D-2 receptors in the anterior pituitary.