Sulpiride Treatment Research Articles

Dopamine D2 receptor antagonist counteracts hyperglycemia and insulin resistance in diet-induced obese male mice.

Obesity leads to insulin resistance (IR) and type 2 diabetes. In humans, low levels of the hormone prolactin (PRL) correlate with IR, adipose tissue (AT) dysfunction, and increased prevalence of T2D. In obese rats, PRL treatment promotes insulin sensitivity and reduces visceral AT adipocyte hypertrophy. Here, we tested whether elevating PRL levels with the prokinetic and antipsychotic drug sulpiride, an antagonist of dopamine D2 receptors, improves metabolism in high fat diet (HFD)-induced obese male mice. Sulpiride treatment (30 days) reduced hyperglycemia, IR, and the serum and pancreatic levels of triglycerides in obese mice, reduced visceral and subcutaneous AT adipocyte hypertrophy, normalized markers of visceral AT function (PRL receptor, Glut4, insulin receptor and Hif-1α), and increased glycogen stores in skeletal muscle. However, the effects of sulpiride reducing hyperglycemia were also observed in obese prolactin receptor null mice. We conclude that sulpiride reduces obesity-induced hyperglycemia by mechanisms that are independent of prolactin/prolactin receptor activity. These findings support the therapeutic potential of sulpiride against metabolic dysfunction in obesity.

Endocrine and ovarian responses to combined estradiol benzoate-sulpiride in seasonally anovulatory mares treated with kisspeptin

The objective of this experiment was to determine if incorporation of kisspeptin-10 (Kp10) into treatment with estradiol benzoate (EB) and sulpiride to induce early cyclicity would result in greater endocrine responses and a greater number of mares responding with either follicle(s) > 30 mm or ovulation within 25 days of treatment. Eighteen anestrous mares were blocked by breed, body condition, and age before random assignment to treatment or control. All mares received 50 mg EB before receiving osmotic minipumps containing either saline (n = 9) or Kp10 (50 μg/hour; n = 9) one day later. The next day, all mares received 3 g sulpiride. Serial blood sampling occurred after pump placement and continued daily for 25 days. Transrectal ultrasounds were performed regularly to monitor ovarian activity. Data were analyzed by Student’s t-test or ANOVA with repeated measures. Seven Kp10-treated mares responded compared to only 4 saline-treated mares. Mean days from sulpiride treatment to ovarian response was less in Kp10-treated mares (13.7 ± 1.1 d, P ≤ 0.01) compared to saline-treated mares (35.9 ± 7.8 d). Plasma prolactin increased (P < 0.001) in response to sulpiride in all mares; however, prolactin was higher (P < 0.05) in Kp10-treated mares. Plasma LH increased in all mares beginning 5 days after sulpiride but was greater (P < 0.0001) in Kp10-treated mares. Plasma FSH concentrations did not differ between groups. In conclusion, incorporation of Kp10 potentiated the prolactin and LH responses to EB-sulpiride and resulted in more mares responding with early ovarian activity.

Evaluation of eight psychoactive drugs used in Chinese cities by wastewater-based epidemiology

With rapid economic development, an increasing number of people suffer from mental health diseases, which are gradually receiving the attention of society. However, basic data from surveys of mental disorders are limited. Composite influent samples were collected from 26 wastewater treatment plants in 23 major cities in China. The concentrations of the psychoactive drugs diphenhydramine, fluoxetine, doxepin, imipramine, sulpiride, zolpidem, carbamazepine, and flunitrazepam in the wastewater were determined. The detection frequency of diphenhydramine, sulpiride, and carbamazepine was close to 100 %, whereas that of the compounds was lower than 35 %. Carbamazepine had the highest mean consumption (31.1 mg/d/1000 people), followed by diphenhydramine (10.4 mg/d/1000 people) and sulpiride (11.3 mg/d/1000 people). Wastewater-based epidemiology (WBE) estimates of the average use of the three drugs were lower than those from the drug statistics data. Consumption of diphenhydramine in northern China was higher than that in southern China. A correlation analysis of psychotropic and illicit drugs revealed a correlation between sulpiride and heroin use, which may be related to the adverse effects of sulpiride treatment after heroin withdrawal. Psychotropic drug use is associated with both economic and social factors. We found associations between the use of the three drugs and age, occupation, and obesity, which are risk factors for mental disorders. The results showed that the monitoring of psychotropic drug using WBE has a certain reference value for public health care and for improving the understanding of mental disorders.

72 Endocrine and ovarian responses to combined estradiol benzoate-sulpiride in anestrous mares treated with kisspeptin

Abstract The objective of this study was to determine if incorporation of kisspeptin 10 (Kp10) into an estradiol benzoate (EB)-sulpiride treatment would result in greater endocrine responses, and a greater number of mares ovulating within 28 days of treatment compared to EB-sulpiride alone. Eighteen anestrous mares were blocked by horse type (light horse and pony crosses), body condition, and age, then randomly assigned to treatment or control. On day 0, all mares received 50 mg EB. On day 1, mini osmotic pumps containing saline (n = 9) or Kp10 (50 mg/hour; n = 9) were inserted subcutaneously in the neck and remained for 7 days. Serial blood sampling occurred for 24 hours after pump placement. On day 2, all mares received 3 g sulpiride. Serial blood sampling continued for 36 hours and daily for 28 days. Transrectal ultrasounds were performed regularly for detection of ovulation. Plasma was assayed for prolactin, luteinizing hormone (LH) and progesterone. Data were analyzed by ANOVA with repeated measures. Plasma prolactin increased (P &amp;lt; .001) in response to sulpiride in all mares and remained stimulated for 7 days. Prolactin responses tended to be greater (P = .09) in Kp10- treated mares compared to controls. No differences were detected in plasma LH during the first 24 hours after pump placement; however, LH increased in all mares beginning 5 days after sulpiride and were greater (P &amp;lt; .05) in Kp10-mares from day 7 to day 21. Eleven of 18 (61%) mares ovulated within 18 days of sulpiride treatment; however, no differences in ovulation dates were detected between Kp10 treated- and control- mares. No differences were detected in plasma progesterone during the first 5 days post ovulation. In conclusion, incorporation of Kp10 potentiated the prolactin and LH responses to EB-sulpiride, but did not further advance first ovulation in treated-mares.

Oral exposure of sulpiride promotes the proliferation of Brown-Norway rat prostates.

: The aim of the present study was to establish an animal model of prostatic hyperplasia to explore the mechanisms of this disease. Sulpiride, a specific type 2 dopamine receptor antagonist, causes prostate toxicity by stimulating prolactin (PRL) production. Male Brown-Norway (BN) rats were treated intragastrically (i.g.) with sulpiride (40 and 120 mg/kg daily) and vehicle (i.g., daily) for 4 weeks. The results demonstrated that sulpiride-treatment resulted in increased prostate size, prostate lobe weight, epithelial height and acinar luminal area. Furthermore, prostate lobe weight, epithelial height and acinar luminal area of lateral lobes (LP) significantly increased. These effects were dose dependent. Sulpiride treatment increased serum PRL, follicle-stimulating hormone and testosterone levels, while serum luteinizing hormone levels were reduced. Immunohistochemical analysis revealed that proliferating cell nuclear antigen and B-cell lymphoma-2 were significantly increased in certain sulpiride treated groups. Furthermore, estrogen receptor (ER)-α and androgen receptors were upregulated, while ERβ was downregulated in LP. The expression of stromal cell biomarkers, including vimentin, fibronectin and α-smooth muscle actin were significantly increased in LP following 40 mg/kg sulpiride administration. These results suggest that sulpiride causes LP hyperplasia in BN rats by promoting proliferation and inhibiting prostate cell apoptosis via ERα and AR signaling.

Morphological and Biochemical Characteristics of Prostate Hyperplasia during Sulpiride Treatment.

We studied morphological changes in the prostate ventral lobe, proliferative activity of the epithelium in prostate acini, and the levels of prolactin and prostate-specific antigen in the blood serum of Sprague-Dawley rats after repeated injections of sulpiride in a dose of 40 mg/ kg over 30 and 60 days and in 10 and 30 days after withdrawal. Morphological and morphometrical analysis of hyperplastic changes in the prostate ventral lobe was performed. Ki-67+ proliferating epithelial cells in the acini were counted. The dynamics of serum concentrations of prolactin and prostate-specific antigen was evaluated by ELISA. Morphological and morphometrical analysis and evaluation of the content of Ki-67+ cells demonstrated epithelium hyperplasia in the prostate ventral lobe after sulpiride treatment for 30 or 60 days and in 10 days after withdrawal, but serum level of prostate-specific antigen did not differ from the control. After 60-day sulpiride treatment and in 30 days after withdrawal, pronounced hyperplastic changes of prostate and elevated concentrations of prostate-specific antigen (but not prolactin) were observed. Thus, administration of sulpiride (40 mg/kg) to Sprague-Dawley rats for 60 days allows, by morphological criteria and serum level of prostate-specific antigen, to model stable hyperplastic changes in the prostate corresponding to benign prostatic hyperplasia in humans.

Оценка корректирующего влияния сульпирида на поведенческие нарушения алкоголизированных самцов белых крыс с разным уровнем депрессивности

The aim of the study was to evaluate correction of behavioral disorders with sulpiride, a dopamine autoreceptor inhibitor, in alcoholized rats taking into account individual typological features of the animals. Methods. Experiments were performed on sexually mature male rats weighing 180-220 g. The level of anxiety was determined in the elevated plus-maze by the total time of stay in and number of exits from the open space of the maze during 5 minutes of testing. Locomotor and exploratory activity and grooming behavior were assessed in the open field for 5 minutes. The severity of animal depression was determined using the standard Porsolt test by the number and total duration of immobility periods. The emotional state of animals was evaluated by the number of fecal boluses. After the initial (control) tests, the rats were divided into three subgroups based on the severity of depression as determined in the Porsolt test. Alcoholism was modeled by intraperitoneal injections of 10% ethanol (2 g/kg body weight) for 14 days. Then the animal behavior was re-tested. Sulpiride (Eglonyl, Sanofi Winthrop Industrie, France) was administered for 14 days at a dose of 10 mg/kg, intraperitoneally; then the animals were tested again. Results. Two-week alcoholization resulted in increased anxiety and depression of rats with low and medium depression degree at baseline. These disorders were evident from shortened stay of these animals in the open space of elevated plus-maze, reduced number of repeated exits from the open space, and a significant increase in the total time of immobility in the Porsolt test. The subsequent sulpiride treatment corrected the anxiogenic and depressogenic effects of alcoholism in male rats of these subgroups. Originally high-depressive animals did not show a sensitivity to the 14 day-administration of ethanol and subsequent inhibition of D2/D3-dopamine receptors in the elevated plus-maze and Porsolt test. Administration of ethanol for 14 days suppressed both the exploratory activity of rats in the open field regardless of their baseline degree of depression, and the locomotor activity of low-depressive animals. The subsequent sulpiride treatment did not abolish the effect of alcohol on the behavioral activity in the open field. Low-depressive alcoholized males developed a depression-like condition characterized by a marked behavioral deficit in the open field. The two-week alcoholization resulted in a significant (2-3.5 times) increase in the emotionality irrespective of the baseline degree of depression. This disorder was fully corrected by the sulpiride treatment in high-depressive rats and partially reduced the signs of emotionality in low- and medium-depressive animals. Conclusion. The study showed a possibility for correction of anxiety and depressive disorders induced by two weeks of modeled alcohol abuse with sulpiride depending on individual typological features of animals.

Influence of sulpiride treatment on the level of prolactin and immunoglobulins in the peripheral blood of mares during the postpartum period.

The aim of this study was to determine the effect of increased levels of prolactin (PRL) on the concentration of immunoglobulins in the blood, colostrum and milk of mares. The study was conducted on 12 mares of the Polish Pony breed (6 in the control and 6 in the experimental group). To induce hyperprolactinaemia in mares of the experimental group, 750 mg sulpiride was administered orally once a day. The initial PRL concentration was 52.22 ± 11.21 ng/ml in the control group and 49.39 ± 10.12 ng/ml in the experimental group. In the subsequent days, the concentration of PRL dynamically changed. Statistical analysis showed highly significant differences (P < 0.01) between the groups. The concentration of immunoglobulins in the blood plasma was at the same level during the experimental period (32.97-29.08 mg/ml in the experimental group and 28.60-18.11 mg/ml in the control group). Statistical analysis showed highly significant differences between the groups in blood plasma immunoglobulin level (P < 0.01). The highest immunoglobulin concentration was obtained within 12 h after parturition in the control and the experimental group (23.49 ± 2.12 mg/ml and 26.94 ±1.72 mg/ml, respectively). The lowest values were obtained on day 12 after parturition in the experimental group (10.15 mg/ml ± 1.47 mg/ml) and on day 7 after parturition in the control group (14.30 mg/ml ± 2.48 mg/ml). In conclusion, this study did not provide evidence that the lactogenic hormone prolactin is involved in the transfer of immunoglobulins into the colostrum in horses.

Preliminary Evaluation of Treatment With Long-Acting Estradiol Cypionate and Sulpiride for Advancing First Ovulation of Year in Postpartum Acyclic Mares

Two preliminary trials were performed to evaluate the efficacy of long-acting estradiol cypionate plus sulpiride treatment for hastening the first ovulation in postpartum acyclic mares. In 2010 (year 1) and 2012 (year 2), mares that had foaled in January or February and that were ≥7 ± 1 day postpartum were teased to a stallion to detect estrus and examined by transrectal ultrasonography 3 times weekly. Mares identified as acyclic were alternately assigned to treatments as follows: year 1—group ECP-SUL (n = 5)—same day intramuscular (IM) injection of 50-mg long-acting estradiol cypionate (ECP) plus 1.5-g long-acting sulpiride (SUL), or CON (n = 5)—control; year 2—ECP-SULX2 (n = 4)—IM injection of 100-mg ECP, followed 2 and 7 days later with IM injection of 1.5-g SUL, or CON (n = 5). When a follicle ≥35 mm in diameter, prominent uterine edema and a relaxed cervix were detected, an ovulation-inducing agent was administered. Examinations continued at 2- to 3-day intervals until ovulation was detected. Median (range) interval to ovulation did not differ in year 1 between SUL-ECP (76 days; 31–90 days) and CON mares (74 days; 35–98 days; P = 1.00), or in year 2 between ECP-SULX2 (48 days; 36–66 days) and CON mares (39 days; 39–71 days; P = .91). The injection of the dopamine antagonist sulpiride in a sustained release form in conjunction with the estrogen ECP failed to shorten the interval to the first ovulation of the year in these two groups of postpartum acyclic mares.

Effects of Stimulation and Blockade of D2 Dopamine Receptors on the Behavior of Gonadectomized Male Rats

The present study aims to perform the comparative assessment of stimulation and blockade for D2-dopaminergic receptors in depression-like behavior in male rats with deficiency of androgen hormones. Two weeks after surgery, GDX rats began 14 days of treatment with vehicle, a low dose of testosterone propionate (0.5 mg/kg, s.c.), quinpirole (0.1 mg/kg, i.p.), sulpiride (10.0 mg/kg, i.p.), quinpirole plus testosterone propionate or sulpiride plus testosterone propionate. The animals were then tested in forced swimming test (FST) and the open field test (OFT). Quinpirole administered alone or in a combination with a low dose of testosterone propionate resulted in antidepressant-like effect in GDX rats in the FST. Repeated treatment of quinpirole and testosterone propionate profoundly increased antidepressant-like effect of the single substances they exert per se. Application of neither quinpirole nor quinpirole plus testosterone propionate led to any changes of behavioral reactions in GDX rats in the OFT, except increased grooming behavior. On the contrary, sulpiride treatment failed to alter depression-like behavior in GDX rats in the FST. In addition, sulpiride blocked the antidepressant-like effect of testosterone propionate in GDX rats and its combination with a low dose of testosterone propionate induced prodepressant-like effect in GDX rats. Co-administration of sulpiride with testosterone propionate or its single application increased frequency of rearing and grooming in GDX rats in the OFT. In summary, the results of the present study suggest that stimulation of D2-dopaminergic receptors results in antidepressant-like effect at androgen deficiency in male rats, while blockade of D2-dopaminergic receptors resulted in prodepressant-like effect.

Induction of ovulation in anestrus ewes using a dopamine receptor antagonist

Estradiol decreases the pulse frequency of LH during the nonbreeding season through dopaminergic neurons that results in anestrus in the ewe. Long-term administration of sulpiride, a dopamine antagonist, induced ovulation in seasonally anestrus mares. Accordingly, we tested whether sulpiride would induce ovulatory estrus in seasonally anestrus Malpura ewes. A total of 12 Malpura ewes were divided into sulpiride (at 0.6 mg/kg b.i.d.) or control groups. Anestrus was defined on the basis of the absence of heat signs for 2 months through twice-a-day heat detection during the nonbreeding season (October–November) and progesterone level of less than 1 ng/mL. Rates of estrus induction, ovulation, multiple ovulations, and lambing in the sulpiride-treated ewes were 83.3%, 100%, 16.6%, and 66.7%, respectively. The mean interval from treatment to estrus was 5.25 ± 1.49 days. Progesterone levels were elevated after ovulation significantly on Days 5 and 7 after estrus as compared to Day 0 after sulpiride treatment (P < 0.05). In contrast, none of the control group ewes showed either estrus or ovulation. There was a significant association between sulpiride treatment and estrus induction rate as well as ovulation rate (P < 0.05). It is concluded that the result provides proof of concept that the dopamine antagonist can induce ovulation in seasonally anestrus ewes.

Assessment of Prolactin and Quantitative Milk Production After Induction of Lactation in Barren Jennies (Equus asinus): A Pilot Study

The secretion of circulating prolactin levels in response to sulpiride treatment was evaluated in eight mature cyclic barren jennies divided into two groups on the basis of different treatments. The experimental group A was submitted to the sulpiride treatment twice a day for nine consecutive days, up to 14 days after ovulation, and the control group B was submitted to the equivalent saline placebo administration. Milking was started at 8 days after ovulation, at 3 days after the beginning of sulpiride treatment, to 28 days after ovulation, and performed five times per day between 09:00 AM and 11:00 PM by hand; the oxytocin treatment was performed (5 IU/head per intramuscular injection) 5 minutes before milking, to facilitate the udder contraction. Blood samples were collected in baseline conditions (the day before the onset of the treatments) from day 0, during all treatment periods, until day 28 after ovulation, from the jugular vein from the each subject, twice a day, at 08:00 AM and at 08:00 PM. Both pluriparous experimental (P < .0005) and control (P < .005) jennies and nulliparous experimental (P < .005) and control (P < .0005) jennies showed higher morning prolactin (PRL) concentrations than afternoon values. Nulliparous experimental jennies showed higher morning (P < .0001) and afternoon (P < .0001) PRL values than nulliparous control jennies. Significant and negative correlation between PRL concentrations and milk production (r = −0.67) was observed only in experimental pluriparous jennies. The present pilot study demonstrates the PRL profiles during and after induction of lactation in barren pluriparous and nulliparous Ragusana jennies.

The efficacy of sulpiride in patients with anxiety disorders depending on the serum serotonin concentrations

The efficacy of sulpiride in patients with anxiety disorders depending on the serum serotonin concentrations was evaluated. We examined 132 patients with anxiety disorders. The higher levels of serotonin were found in 81 (61.3%) of patients, normal levels in 24 (25.8%) and lower levels in 27 (20.5%). Sulpiride was used in doses from 50 to 400 mg. Average treatment duration was >90 days. The positive effect of sulpiride monotherapy was identified in patients with higher and normal levels of serotonin. No clinical effect of sulpiride was noted in patients with lower serotonin concentrations. The efficacy of sulpiride depends on serum concentrations of serotonin. It can be assumed that serotonin concentration is a marker of sulpiride treatment efficacy in patients with anxiety disorders.

The Effect of Sulpiride Treatment During the Periovulatory Period on Prolactin Concentration and Ovulation in the Mare

Sixteen estrous cycles from 10 cyclic mares were randomly assigned to a control or sulpiride group (n = 8 each). All mares received 1,500 IU of human chorionic gonadotropin (hCG) (hour 0) during estrus with a follicular diameter ≥32 mm. Mares were scanned every 12 hours until ovulation. In the treatment group, beginning at hour 0, each mare received 1.5 mg/kg of sulpiride every 12 hours intra-muscularly until ovulation or formation of a luteinized unruptured follicle (LUF). Concentrations of luteinizing hormone (LH) and prolactin (PRL) were measured by radioimmunoassay. In each group, there were 10 preovulatory follicles for the eight cycles. The ovulation rate (9/10, 90%) was similar in the control and sulpiride groups. Two mares formed an LUF, which was first detected at hours 48 and 72 for the sulpiride and control mares, respectively. The interval from hCG to ovulation was 49.5 ± 11.1 and 43.5 ± 5.8 hours, for the control and sulpiride groups, respectively (P > .5). LH followed the typical preovulatory surge pattern, with no difference between groups (P > .5). Sulpiride administration increased PRL concentration in treated mares at 24 (P < .1), 36, and 48 hours (P < .05) after treatment. In conclusion, sulpiride administration every 12 hours increased PRL concentration in treated mares after 24 hours of the beginning of treatment. However, at this time window and concentration, PRL did not have any effect on ovulation. The control mare that developed an LUF had a PRL concentration similar to other ovulatory control mares (always ≤10 ng/mL).

Detecting Potential Adverse Reactions of Sulpiride in Schizophrenic Patients by Prescription Sequence Symmetry Analysis

PurposePrevious studies have demonstrated sulpiride to be significantly more effective than haloperidol, risperidone and olanzapine in schizophrenic treatment; however, only limited information is available on the potential risks associated with sulpiride treatment. This study attempts to provide information on the potential risks of sulpiride treatment of schizophrenia, especially with regard to unexpected adverse effects.Materials and MethodsPatients with schizophrenia aged 18 and older, newly prescribed with a single antipsychotic medication from the National Health Insurance Research Database of Taiwan in the period from 2003 to 2010 were included. A within-subject comparison method, prescription sequence symmetry analysis (PSSA) was employed to efficiently identify potential causal relationships while controlling for potential selection bias.ResultsA total of 5,750 patients, with a mean age of 39, approximately half of whom were male, constituted the study cohort. The PSSA found that sulpiride was associated with EPS (adjusted SR, 1.73; 95% CI, 1.46–2.06) and hyperprolactinemia (12.04; 1.59–91.2). In comparison, EPS caused by haloperidol has a magnitude of 1.99 when analyzed with PSSA, and hyperprolactinemia caused by amisulpride has a magnitude of 8.05, respectively. Another finding was the unexpected increase in the use of stomatological corticosteroids, emollient laxatives, dermatological preparations of corticosteroids, quinolone antibacterials, and topical products for joint and muscular pain, after initiation of sulpiride treatment.ConclusionsWe found sulpiride to be associated with an increased risk of EPS and hyperprolactinemia, and the potential risk could be as high as that induced by haloperidol and amisulpride, respectively. Additionally, our study provides grounds for future investigations into the associations between sulpiride and the increased use of additional drugs for managing adverse effects, including stomatological, dermatological, and musculoskeletal or joint side effects, constipation, and pneumonia.

Effect of sulpiride treatment during the periovulatory period on ovulation and LUF formation

The most common pathological anovulatory condition that occurs in the mare is the hemorrhagic anovulatory follicle (HAF). The exact cause is still unknown, but it is likely that many factors are involved in the inhibition of follicle rupture. The inhibition of prostaglandin synthesis by flunixin-meglumine during the periovulatory period resulted in a high percentage of luteinized unruptured follicles (LUF) in the mare [Cuervo-Arango et al., Theriogenology 2011; 76: 361-73]. High plasma prolactin (PRL) has been regarded as another possible cause of LUF. A recent study showed a 56% incidence on LUF development in mares with high PRL concentration after long term treatment with sulpiride [Zagrajczuk and Okolski, Reprod Dom Anim 2010;45(Suppl.3):62]. In vitro experiments have demonstrated that PRL during the periovulatory period inhibits ovulation by reducing ovarian plasmin generation in rabbits (Yoshimura et al., 1994). The aim of the present study was to determine the effect of sulpiride on ovulation during the periovulatory period in mares. Sixteen estrous cycles from 10 cyclic mares between February and June in Spain were randomly assigned to a control or sulpiride group (n1⁄48 each). All mares received 1500 IU of hCG (Hour 0) when they reached a follicular diameter 32 mm and presence of endometrial oedema. Mares were scanned every 12 h until ovulation or LUF formation. In the

Effect of Noise Stress on Lung and Heart of the Adult Albino Rats and the Possible Protective Role of Sulpiride

Abstract: Exposure to crowding stress is associated with increased respiratory system morbidity, However, the underlying mechanisms are unclear. Thus, there is a need for more study of this harmful effect. Sulpiride had been shown to have a protective role against crowding stress on other systems but this role was not studied well on the respiratory and cardiovascular systems. Objectives: Investigating the possible harmful effects of crowding on adult albino rats' lung and heart and the possible protective role of combined sulpiride treatment. Materials and Methods: The present study was carried out on 24 adult albino rats of local strain weighing 120±3 g which were randomly divided equally into Group 1(C, untreated negative control), Group 2 (Cr, crowding exposed or positive control) where rats were exposed to crowding in a cage (20x20x20 cm- 6 rats /cage) for 1 month, Group 3(D, sulpiride-treated) where the rats were exposed to sulpiride “0.028 mg/B.W./day” and Group 4 (Cr+D, crowding + sulpiride-treated). Paraffin sections were prepared for histological, histochemical and morphometric studies. The data were statistically analysed. Results: The rats exposed to crowding only or sulpiride only showed highly significant damaging changes on lung such as thickening in the interalveolar septa and obliteration of the alveoli, inflammatory cells infiltration within the pulmonary interstitium, peribronchiolar infiltration and fibrosis, thickening of the pulmonary blood vessels walls, interstitial collagen fibres deposition and apoptotic cellular changes. On the level of heart, significant decrease in the diameters of the myocardial muscle fibres with focal areas of necrosis, apoptotic changes and increased collagen fibres deposition was marked in sulpiride group. When crowding and sulpiride treatments were combined, the damaging effects were maximized on the lung and heart. Conclusion: These results provided evidence that crowding stress causes obvious lung and heart tissue damages. No protective role for sulpiride was proofed. This is because using sulpiride alone or in combination with crowding showed marked damaging effects on the lung and heart tissues.

Anxiolytic-like effect of quinpirole in combination with a low dose of 17β-estradiol in ovariectomized rats

The aim of this study was to explore effects on anxiety-like behavior of the D2 dopamine receptor agonist, quinpirole and of the D2 dopamine receptor antagonist, sulpiride given alone or in combination with a low dose of 17β-estradiol (17β-E2) to ovariectomized (OVX) rats. Two weeks after surgery, OVX rats began 14 days of treatment with the vehicle, a low dose of 17β-E2 (5.0 μg/rat, s.c.), quinpirole (0.1 mg/kg, i.p.), sulpiride (10.0 mg/kg, i.p.), quinpirole plus 17β-E2 or sulpiride plus 17β-E2. The animals were then tested in the black and white model (BWM) and the open field test (OFT). Quinpirole (0.1 mg/kg, i.p.) administered alone or in a combination with a low dose of 17β-E2 (5.0 μg/rat, s.c.) resulted in anxiolytic-like effect in OVX rats in the BWM. Repeated treatment of quinpirole and 17β-E2 profoundly increased anxiolytic-like effect of the single substances they exert per se. Co-administration of quinpirole with 17β-E2 increased frequency of rearing and grooming in OVX rats in the OFT. Sulpiride (10.0 mg/kg, i.p.) treatment failed to alter anxiety-like behavior in OVX rats in the BWM. In addition, sulpiride blocked the anxiolytic-like effect of 17β-E2 in OVX rats. Application of neither sulpiride nor sulpiride plus 17β-E2 led to any changes of rearing and grooming behavior in OVX rats in the OFT. The results of the present study suggest that 17β-E2 and quinpirole interact to exert anxiolytic-like action and that each of these drugs can potentiate effects of each other. Further research is needed to elucidate detailed mechanisms by which quinpirole and 17β-E2 exert synergistic effect on anxiety-related behavior.

Valproate Alters Dopamine Signaling in Association with Induction of Par-4 Protein Expression

Chromatin remodeling through histone modifications has emerged as a key mechanism in the pathophysiology of psychiatric disorders. Valproate (VPA), a first-line medication for bipolar disorder, is known to have histone deacetylase (HDAC) inhibitor activity, but the relationship between its efficacy as a mood stabilizer and HDAC inhibitory activity is unclear. Here we provide evidence that prostate apoptosis response-4 (Par-4), an intracellular binding partner of dopamine D2 receptors (DRD2), plays a role in mediating the effectiveness of VPA. We found that chronic VPA treatment enhanced the expression of Par-4 in cultured neurons and adult mouse brains. This Par-4 induction phenomenon occurred at the transcriptional level and was correlated with an increase in histone H3 and H4 acetylation of the Par-4 promoter regions. Furthermore, chronic VPA treatment potentiated the suppression of the cAMP signaling cascade upon dopamine stimulation, which was blocked by sulpiride treatment. These results indicate that VPA potentiates DRD2 activity by enhancing Par-4 expression via a chromatin remodeling mechanism.

Ovarian and PGF2α responses to stimulation of endogenous PRL pulses during the estrous cycle in mares

The effects of a PRL-stimulating substance (sulpiride) on PRL and PGF2α secretion and on luteal and ovarian follicular dynamics were studied during the estrous cycle in mares. A control group (n = 9) and a sulpiride group (Sp; n = 10) were used. Sulpiride (25 mg) was given every 8 h from Day 13 postovulation to the next ovulation. Repeated sulpiride treatment did not appear to maintain PRL concentrations at 12-h intervals beyond Day 14. Therefore, the hypothesis that a long-term increase in PRL altered luteal and follicular end points was not testable. Hourly samples were collected from the hour of a treatment (Hour 0) to Hour 8 on Day 14. Concentrations of PRL increased to maximum at Hour 4 in the Sp group. The PRL pulses were more prominent (P < 0.008) in the sulpiride group (peak, 19.4 ± 1.9 ng/mL; mean ± SEM) than in the controls (11.5 ± 1.8 ng/mL). Concentrations of a metabolite of PGF2α (PGFM), number, and characteristics of PGFM pulses, and concentrations of progesterone during Hours 0 to 8 were not affected by the increased PRL. A novel observation was that the peak of a PRL pulse occurred at the same hour or 1 h later than the peak of a PGFM pulse in 8 of 8 PGFM pulses in the controls and in 6 of 10 pulses in the Sp group (P < 0.04), indicating that sulpiride interfered with the synchrony between PGFM and PRL pulses. The hypothesis that sulpiride treatment during the equine estrous cycle increases concentrations of PRL and the prominence of PRL pulses was supported.