Sulpiride Treatment Research Articles

Sulpiride treatment of acute mania with a comparison of the effects on plasma hormone concentrations of lithium and sulpiride treatment

Sulpiride, in this open study of acute manic patients, had a clear antimanic action with all eight patients responding to sulpiride treatment without the need for other antipsychotic drugs. Plasma prolactin concentrations were increased and oestrogen-stimulated neurophysin concentrations decreased by sulpiride but were unchanged by lithium treatment, whereas TSH concentrations showed a rapid increase following the introduction of lithium therapy.

Dopamine D 2 and muscarinic receptor binding characteristics in rat brain after withdrawal of subchronic fluphenazine and sulpiride treatment

1. The effects of subchronic (10 days) treatment with two antischizophrenic drugs, fluphenazine and sulpiride, on rat brain dopamine and muscarinic receptor sites were studied at various time points after withdrawal from the drug treatments. Striatal D-2 dopamine receptors and cortical muscarinic receptors were characterized with the radioligands 3H-spiperone and 3H-quinuclidinyl benzilate ( 3HQNB), respectively. 2. Neither drug treatment affected significantly the number or affinity of cortical muscarinic receptors during the withdrawal time of 18 days. 3. The number of D-2 receptors in striatum was not altered after 4 or 8 fluphenazine-free days, but after 18 days fluphenazine caused an increase of 55 % in the density of D-2 receptors. Sulpiride caused a slight increase in Bmax of striatal D-2 receptors after 4 and 8 withdrawal days but the maximum increase of 29 % was observed after 18 withdrawal days. 4. Fluphenazine treatment caused an increase in the apparent dissociation constant 4 days after the termination of the treatment suggesting that residual neuroleptic levels may have been retained after this dose regimen, since the Kd returned near control levels as the withdrawal time passed. Sulpiride, however, caused a moderate increase in Kd throughout the withdrawal time. 5. In conclusion, these results suggest that even a rather short treatment with fluphenazine or sulpiride, a classical and an atypical neuroleptic, respectively, can induce pronounced changes in striatal dopamine receptor characteristics after a drug washout period of almost three weeks. Thus, possible delayed actions of classical as well as novel neuroleptic drugs on neurotransmitter function should be considered in studies examining the neuroleptic withdrawal effects.

Differences in the time course of dopaminergic supersensitivity following chronic administration of haloperidol, molindone, or sulpiride

The onset and persistence of changes in 3H-spiroperidol binding to dopamine (DA) D2 receptors were examined in rat mesolimbic and striatal brain regions following daily administration of haloperidol, molindone, or sulpiride for 3, 7, 14, or 28 days. Neuroleptic dose equivalencies were determined by inhibition of 3H-spiroperidol in vivo binding in several rat brain regions. Changes in locomotor and stereotyped responses to the specific DA D2 agonist quinpirole were examined 3 days after the last treatment dose. Haloperidol or molindone administration increased mean stereotypy scores and striatal DA D2 receptor densities throughout the 28-day treatment period. In contrast, mesolimbic DA D2 receptor densities were transiently increased and returned to control values, after 28 days of haloperidol or molindone treatment. Sulpiride treatment increased mean stereotypy scores and striatal Bmax values, but had no effect on locomotion or mesolimbic dopamine receptor density. Additionally, the magnitude of change in the various measures of brain DA function varied among the three neuroleptic treatment groups. Results from this study suggest that mesolimbic and striatal brain regions differ in their response to long-term neuroleptic administration and that drug choice may influence the magnitude of neuroleptic-induced dopaminergic supersensitivity.

Involvement of postnatal gonads in the maturation of dopaminergic regulation of prolactin secretion in female rats.

Permanent effects of postnatal gonads on dopamine (DA)-mediated regulation of PRL secretion were examined in adult female rats of the Wistar-Imamichi strain. Experiments were uniformly done at the age of about 10 weeks. First, rats were bilaterally ovariectomized on varying postnatal days, i.e. 24 h after birth [neonatal castration (NC)] or at 1, 2, 3, 4, or 6 weeks of age. Intact diestrous females were also examined. All groups were injected ip with saline or sulpiride (1 mg/kg BW), and blood samples were collected by rapid decapitation 20 min later. Also, in saline control groups, the anterior pituitary (AP) PRL content was determined. In NC females, significant PRL release was not observed by either sulpiride or saline. However, stimulation of PRL release by sulpiride was observed consistently in rats ovariectomized on or after 1 week of age. Although there was not a complete correlation between the plasma PRL level attained after sulpiride treatment and the AP PRL content, the general trend was that the AP PRL content was increased as the postnatal age of the ovariectomy was delayed. Values in intact adult females exceeded those in all of the castrated groups in both parameters. Second, daily sc injection for 7 days with estradiol benzoate (E2; 2.5 micrograms/kg BW) and/or progesterone (P; 5 mg/kg BW) was given after NC to determine which ovarian secretion(s) is involved in the aforementioned findings. Sulpiride stimulated PRL release in NC females that had been treated neonatally (postnatal days 3-9) with either E2 or P. This effect was accompanied by an increase in the AP PRL content. An enhancement of both parameters was also observed when the same dose of E2 or P was given in the fourth week (postnatal days 22-28). However, neither parameter was further augmented by concurrent administration of E2 and P at either postnatal time. Characteristics of AP DA receptors were subsequently analyzed in some of the foregoing groups using [3H]spiperone. The number of binding sites, when expressed as femtomoles per pituitary, did not differ among all groups examined. However, a significant difference in the dissociation constant (Kd) was observed between NC females and females castrated at 6 weeks of age. The Kd in NC females was not altered by subsequent neonatal treatment with E2 and/or P. Nonetheless, the E2 effect on Kd was dependent on when E2 was given after NC.(ABSTRACT TRUNCATED AT 400 WORDS)

Subchronic haloperidol and sulpiride treatment induces region-specific changes in tissue levels of putative amino acid transmitters in rat brain

The effect of 10 days treatment with haloperidol (0.5 or 2 mg/kg/day) or sulpiride (10 or 100 mg/kg/day) on regional brain tissue levels of GABA, glutamate, aspartate and glutamine was studied in the rat. The GABA levels were increased in the nucleus (nuc.) accumbens and striatum by haloperidol, but not by sulpiride. The glutamate and glutamine levels were increased in the nuc. accumbens by both drugs. The aspartate levels were increased in the nuc. accumbens by sulpiride. Tissue levels of all 4 amino acids studied remained unchanged in the substantia nigra following the drug treatment. These results indicate that dopaminergic activity has a region-specific influence on the utilization of aspartate, glutamate and GABA in rat brain.

Modulation of ovarian LH receptor and serum hormone levels in rats with hyperprolactinemia induced by administration of ovine prolactin or sulpiride.

Hyperprolactinemia was experimentally produced in rats by administration of ovine prolactin (oPRL) and sulpiride, and tried to evaluate the effect of hyperprolactinemia on ovarian receptor for luteinizing hormone (LH) as well as that on serum gonadotropin and steroid hormone levels. Wistar-Imamichi strain mature female rats showing 4-day estrous cycles were treated with various doses of oPRL or sulpiride twice a day for 4 days from diestrus. They were killed on the fifth day. Binding of ovarian LH receptors was reduced by a small dose of oPRL (0.1 IU) or sulpiride (0.25 mg) and restored to normal by larger doses of oPRL. However, larger doses of sulpiride (50 or 100 mg) increased the receptor bindings beyond the control level (4.39 +/- 0.40 ng/mg homogenate protein). Serum prolactin levels decreased in rats treated with larger doses of oPRL, but increased with larger doses of sulpiride. Serum LH levels increased with both agents. Although the ovaries treated with either oPRL or sulpiride suggested the lack of ovulation, there were no significant changes of steroid hormones in oPRL groups. In contrast, sulpiride treatment resulted in a reduction of estradiol and an increase of progesterone secretion, suggesting the prolonged effect of the drug. Thus, prolactin appeared to act on the rat ovarian LH receptors in two different manners in hyperprolactinemia, depending on the amount of this hormone or a ratio of prolactin to LH.

Influence of chronic hyperprolactinemia induced by sulpiride on the hypothalamo-pituitary-testicular axis in normal men.

For elucidation of the effects of hyperprolactinemia on the hypothalamic-pituitary-testicular axis, five healthy men were exposed to sulpiride (300 mg/day by mouth); four among the five maintained hyperprolactinemia (71.6 to 95.3 ng/ml) for 78 days. Clomiphene citrate (CC), luteinizing hormone (LH)-releasing hormone, and human chorionic gonadotropin tests were performed before and after sulpiride treatment. The CC test, given as a measure of hypothalamic function, was carried out in each of the five volunteers before sulpiride treatment (control) and on days 14 (2 weeks) and 60 (2 months) of sulpiride administration. Each value of plasma LH stimulated by CC was integrated and expressed as a ratio of the integrated value obtained after administering CC at 2 weeks and 2 months to that from each control experiment. The mean ratio in the four subjects at 2 months (mean +/- standard deviation, 0.769 +/- 0.121) was significantly lower than that at 2 weeks (0.942 +/- 0.073; P less than 0.05) and before sulpiride treatment (1.000; P less than 0.01). Impairment of LH responses to CC by 2-month long sulpiride-induced hyperprolactinemia suggests that chronic hyperprolactinemia in men partly suppresses LH secretion by its inhibitory action on the hypothalamus.

Sulpiride-induced hyperprolactinemia and impotence in male psychiatric outpatients

1. The relationship between erectile dysfunction and sulpiride stimulatory effect on prolactin secretion was studied in 13 married male psychiatric outpatients. 2. The patients population was comprised of 2 groups: patients with anxiety disorders resistant to minor tranquilizers who were treated with sulpiride up to 200 mg/day, and schizophrenic patients treated with sulpiride 600 mg/day. All the patients were maintained on maximal dose for a period of 3 weeks. Sexual function and blood prolactin levels were monitored once weekly. 3. The patients who developed impotence were maintained on higher doses of sulpiride and exhibited higher prolactin levels in comparison to the potent patients. 4. Restoration of potency was observed after reduction or discontinuation of sulpiride treatment. 5. It is concluded that sulpiride induced impotence is associated with hyperprolactinemia.

Differential effects of continuous administration for 1 year of haloperidol or sulpiride on striatal dopamine function in the rat

Administration of haloperidol (1.4-1.6 mg/kg/day) for up to 12 months or sulpiride (102-109 mg/kg/day) for between 6 and 12 months increased the frequency of purposeless chewing jaw movements in rats. N,n-propylnorapomorphine (NPA) (0.25-2.0 mg/kg SC) did not induce hypoactivity in haloperidol-treated rats at any time; sulpiride treatment for 9 and 12 months caused a reduction in the ability of NPA to induce hypoactivity. Haloperidol, but not sulpiride, treatment enduringly inhibited low dose apomorphine effects (0.125 mg/kg SC). After 12 months, stereotypy induced by high doses of apomorphine (0.5-1.0 mg/kg) was exaggerated in haloperidol-, but not sulpiride-treated rats. Bmax for specific striatal 3H-spiperone binding was increased by haloperidol, but not sulpiride, treatment throughout the study. Bmax for 3H-piflutixol binding was not altered by chronic haloperidol or sulpiride treatment. Striatal dopamine-stimulated adenylate cyclase activity was inhibited for the 1st month of haloperidol treatment, thereafter returning to control levels; dopamine stimulation was increased after 12 months of sulpiride treatment. Striatal acetylcholine content was increased after 3 and 12 months of treatment with haloperidol, but was not affected by sulpiride. Chronic administration of sulpiride does not induce identical changes in striatal dopamine function to those caused by haloperidol.

Differential alterations in striatal dopamine receptor sensitivity induced by repeated administration of clinically equivalent doses of haloperidol, sulpiride or clozapine in rats.

Rats received therapeutically equivalent doses of either haloperidol (1.7-1.9 mg/kg/day), sulpiride (112-116 mg/kg/day) or clozapine 30-35 mg/kg/day) continuously for 4 weeks. Treatment with haloperidol, but not sulpiride or clozapine, caused inhibition of stereotyped behaviour induced by apomorphine (0.125-0.25 mg/kg SC). Following drug withdrawal for up to 7 days, haloperidol and sulpiride, but not clozapine treatment caused an exaggeration of stereotyped behaviour induced by apomorphine. Bmax values for striatal 3H-spiperone binding were elevated in animals treated for 2 and 4 weeks with haloperidol, but not with sulpiride or clozapine. Following drug withdrawal, haloperidol, but not sulpiride or clozapine, treatment caused an increase in Bmax for striatal 3H-spiperone binding. Bmax values for striatal 3H-NPA binding revealed no change during haloperidol or clozapine treatment. Sulpiride treatment for 1 week caused an increase in Bmax for 3H-NPA binding, which returned to control levels at 2 and 4 weeks. Following drug withdrawal, there was an increase in Bmax for 3H-NPA binding in rats treated with haloperidol and sulpiride, but not clozapine. On continuous treatment and following withdrawal from haloperidol, sulpiride, or clozapine the ability of dopamine to stimulate striatal adenylate cyclase activity did not differ from that in control animals. Repeated administration of sulpiride or clozapine may not induce striatal dopamine receptor supersensitivity when given in clinically relevant doses, although haloperidol does.

Effects of sulpiride treatment on the levels of immunoreactive β-endorphin in rat hypothalamic nuclei

The effects of sulpiride, a specific dopamine receptor antagonist, on the levels of immunoreactive β-endorphin (ir-β-END) in discrete hypothalamic nuclei of rats were investigated. Single injections of sulpiride significantly decreased the levels of ir-β-END in the nucleus arcuatus, nucleus paraventricularis and median eminence. Repeated injections of sulpiride significantly increased the levels of ir-β-END in the nucleus arcuatus, nucleus periventricularis and median eminence. These findings suggest that β-endorphinergic neurons are under dopaminergic control.

Effect of sulpiride on the adenohypophysis of castrated male rats. Immunocytochemistry and ultrastructural cytomorphometry.

Previous studies have shown that N-[(1-ethyl-2-pyrrolidinyl)methyl] )-2-methoxy-5-sulfamoylbenzamide (sulpiride), a psychotrophic drug of clinical use, is a potent antidopaminergic agent, and acts on prolactin and gonadotroph secretions. Cytological changes caused by the effects of this drug were studied in castrated male rats treated with daily doses of sulpiride 5 mg/100 g body weight. Animals were sacrificed 2 months after treatment and their hypophyses processed for cytological and immunohistochemical studies. Cytomorphometry was carried out at the ultrastructural level. An immunocytochemical study was performed with peroxidase-labelled antibody to determine PRL, FSH and LH hormones in gland sections. The administration of sulpiride produced a decrease in granules of prolactin cells. Only the Golgi region showed a positive prolactin reaction and the cytomorphometric study indicated an increase of the area occupied by the endoplasmic reticulum and Golgi complex. In gonadotrophs, treatment with sulpiride decreased the vacuolatin caused by castration. The area occupied by the endoplasmic reticulum was smaller, whereas that occupied by secretion granules and lysosomes became larger. It is suggested that sulpiride treatment increased markedly the mammotroph activity and decreased the gonadotroph one, restoring the vacuolation of the endoplasmic reticulum vacuolation to normal.

Effects of sulpiride induced hyperprolactinemia on testosterone secretion and metabolism before and after HCG in normal men.

The purpose of the study was to investigate the effects of sulpiride-induced hyperprolactinemia on testicular functions, as assessed by evaluation of plasma testosterone (T), dihydrotestosterone (DHT) and 17 beta-estradiol (E2) levels. An HCG test (5000 IU on three consecutive days) was performed in basal conditions and after 12 and 26 days of sulpiride treatment (150 mg daily) in 7 male volunteers, 19 to 32 years of age, as well as in 6 sulpiride-free controls. The results show that after 12 days of induced hyperprolactinemia (mean increase 400%) the T response to HCG was similar to basal test; after 26 days however, the increase of T mean plasma levels was significantly greater. The increase in E2 significantly correlated to that of T during the first and second HCG tests, but no longer after 26 days of hyperprolactinemia, resulting in an imbalance of the E2/T ratio of plasma increments. The response of DHT to HCG was significant in basal conditions and after 26 days of sulpiride and always correlated with T behavior. Data obtained in our experimental conditions suggest that PRL might enhance T secretion. 5 alpha-reductase activity seemed to be partially affected after 12 days of treatment, while a significant inhibition seemed to be exerted on aromatase activity.

Effect of sulpiride-induced hyperprolactinaemia on catecholamine turnover and LRH concentration in the medial basal hypothalamus of rats.

In order to clarify the mechanism of hyperprolactinaemic anovulation, the medial basal hypothalamic (MBH) catecholamine (CA) turnover and LRH concentration, and the serum levels and pituitary contents of gonadotrophins and prolactin (Prl) in hyperprolactinaemic female rats were examined. Hyperprolactinaemia (HPrl) was produced by oral administration of sulpiride for 10 consecutive days; each measurement made on the sulpiride-treated rats was compared with that of control dioestrus rats. Prl, LH, FSH and LRH were determined by radioimmunoassay; CA turnover, as assessed by the accumulation of CA following monoamine oxidase inhibition, was assayed by high performance liquid chromatography with electrochemical detection. Sulpiride treatment induced (1) an increase in the serum Prl and a decrease in the serum LH, (2) an increase in the pituitary FSH and LH contents, (3) an increase in the MBH LRH concentration, and (4) an increase in the MBH dopamine (DA) turnover. These results suggest that HPrl may induce anovulation by impaired LH secretion which was caused by the suppression of LRH release due to an increase in DA turnover in the MBH.

Cerebral glutamate, neuroleptic drugs and schizophrenia: increase of cerebrospinal fluid glutamate levels and decrease of striate body glutamate levels following sulpiride treatment in rats.

Chronic (12 days) administration of sulpiride (50 mg/kg, i.p.) in rats resulted in a significant (12%) increase in the glutamate contents of cerebrospinal fluid. Sulpiride had no effect on the GABA content of the brain areas investigated (frontal cortex, striatum, hippocampus and substantia nigra). Sulpiride is a neuroleptic drug which is believed to block especially the non-adenylate cyclase dopaminergic receptors which are supposed to be inhibitory axoaxonic receptors on glutamatergic corticostriatal terminals. The results are compatible with the hypothesis that glutamatergic hypofunction might be the primary defect in schizophrenia rather than hyperactivity of the dopamine synapses.

Regulation of prolactin and thyrotrophin secretion during human pregnancy: effect of sulpiride and TRH administration.

Abstract. The regulation of prolactin (Prl) and thyrotrophin (TSH) secretions during early human gestation was studied in 30 healthy women. Twelve women were treated with oral sulpiride, 150 mg daily for two weeks, and the Prl and TSH responses to 220 μg of iv thyrotrophin-releasing hormone (TRH) were measured before and at the end of sulpiride administration. Eight women were given 200 mg of sulpiride im, and 4 of them received 200 μg of TRH 30 min later. In 4 women the order of the TRH and sulpiride injections was reversed. Six women were studied as controls. Oral sulpiride treatment induced a significant Prl elevation from 14.6 ± 1.8 μg/l (mean ± sem) to 83.0 ± 4.0 μg/l, whereas the mean TSH levels did not change. Before sulpiride intake, TRH caused a mean maximal increment of 42.9 ± 4.7 μg/l in the Prl levels and an increment of 5.6 ± 0.9 IU/l in the TSH levels. During sulpiride administration, TRH caused a mean maximal increment of 16.5 ± 4.7 μg/l in the Prl levels and 3.5 ± 0.6 IU/l in the TSH levels. Both responses were significantly smaller (P < 0.001) during the sulpiride treatment than before. Intramuscular injection of sulpiride raised the mean Prl concentration by 282 ± 32 μg/l (P < 0.001) and the mean TSH concentration by 0.5 ± 0.1 IU/l (P < 0.05). The Prl elevation was 502 ± 109 μg/l when sulpiride was injected after TRH. A preceding im sulpiride injection caused no changes in Prl and TSH responses to TRH. These results show that in addition to Prl also TSH secretion is partially controlled by the dopaminergic system during early human pregnancy.

Hyperprolactinaemia does not affect the development of the stimulatory mechanism of oestrogen-progesterone on LH secretion.

Abstract. Previous reports indicate that prolactin induces precocious puberty in the female rat. The present investigation was designed to determine if hyperprolactinaemia affects the development of the stimulatory effect of oestrogen-progesterone on LH secretion in prepubertal rats. Hyperprolactinaemia was induced by the administration of sulpiride at the dose of 7 mg/100 g body weight/day for 6 days. The rats were sacridied 6 to 9 h after the last injection. Normal sulpiride-treated rats were injected 76 h before sacrifice with 10 μg of oestradiol benzoate and with 1 mg of progesterone on the day of sacrifice. The animals were killed at 14, 22, 24, 28 and 32 days of age. The sulpiride treatment induced a significant increase in serum prolactin levels (P < 0.01) at all ages studied. The treatment of oestrogen-progesterone induced prolactin release in controls and in the sulpiride-hyperprolactinaemic rats of 24, 28 and 32 day old but not in younger rats. The administration of oestrogen-progesterone alone in normal and in sulpiride hyperprolactinaemic rats produced a negative feed-back effect on LH secretion at 14 and 22 days of age and a significant stimulatory action at 24, 28 and 32 days. No differences were observed in the basal LH serum concentration between control and hyperprolactinaemic rats at the different ages studied. Our findings suggest that the modifications in the onset of puberty induced by hyperprolactinaemia are not connected with alterations in the maturation of the hypothalamic-pituitary mechanism involved in the positive feed-back effect of ovarian steroids on LH secretion.

Possible role of prolactin in the modification of medial basal hypothalamic glutamic acid decarboxylase activity

The effects of acute and chronic injections of haloperidol, sulpiride and apomorphine on serum prolactin (PRL) levels and medial basal hypothalamus (MBH) glutamic acid decarboxylase (GAD) activity were investigated in male rats. Parallel changes in PRL and GAD activity were observed in acutely treated animals. Conversely, a return to normal of the GAD activity associated with high plasma PRL levels was induced by chronic haloperidol and sulpiride treatment. Results are discussed in the light of the possible existence of a hypothetical PRL-γ-aminobutyric acid (GABA) subsidiary feedback loop.

Sulpiride treatment during early human pregnancy: effect on the levels of prolactin, six steroids, and placental lactogen.

To study the role of PRL in the regulation of the production of 17 beta-estradiol, progesterone, testosterone, and human placental lactogen (hPL), 11 healthy women were given 150 mg sulpiride daily for 14 days, beginning between weeks 6--9 of normal gestation. Plasma PRL, estradiol, progesterone, testosterone, and hPL were measured before and 1 and 2 weeks after the start of sulpiride treatment, and the results were compared with those from 16 control women who were followed similarly but without sulpiride treatment. Sulpiride treatment induced significant (P less than 0.001) elevations of plasma PRL at 1 week [84.1 +/- 4.9 vs. 23.7 +/- 2.8 ng/ml (mean +/- SE)] and 2 weeks (83.0 +/- 4.1 vs. 31.9 +/- 4.1 ng/ml). No differences were observed in the concentrations of estradiol, progesterone, testosterone, or hPL. Two women treated with sulpiride reported mild uterine contractions, but no spontaneous abortion occurred in either group. It is evident that hyperprolactinemia or sulpiride treatment do not change the circulating concentrations of sex steroids and hPL between 6--11 of normal gestation.

Effects of drugs on the formation of 3-methoxytyramine, a dopamine metabolite, in the substantia nigra, striatum, nucleus accumbens and tuberculum olfactorium of the rat.

Abstract 3-Methoxytyramine (3-MT) was assayed with a sensitive and rapid liquid chromatographic separation on a Sephadex G 10 column in combination with a fluorimetric detection in a continuous flow system. The method made it possible to measure pargyline-induced 3-MT concentrations in various regions of a single rat brain. After haloperidol, morphine or sulpiride treatment, pargyline-induced 3-MT concentrations in the striatum, nucleus accumbens, tuberculum olfactorium and substantia nigra of the rat were comparable with reported changes of homovanillic acid concentrations. Dose-response curves for 3-MT increase in various brain regions after (+)-amphetamine pretreatment were studied. The effect of (+)-amphetamine on 3-MT formation was much more pronounced in nerve terminal areas, especially in the mesolimbic structures. The influence of apomorphine, γ-hydroxybutyric acid, haloperidol, reserpine or combined treatment of haloperidol and (+)-amphetamine revealed pronounced differences on regional 3-MT concentrations, indicating important differences between the regulation of dopamine metabolism in the substantia nigra and nerve terminal areas.