Cannabidiol impairs the rewarding effects of methamphetamine: Involvement of dopaminergic receptors in the nucleus accumbens.

Cannabidiol, as component of cannabis, can potentially hinder the rewarding impact of drug abuse; however, its mechanism is ambiguous. Moreover, the nucleus accumbens (NAc), as a key area in the reward circuit, extensively receives dopaminergic projections from the ventral tegmentum area. To elucidate the role of accumbal D1 and D2 dopamine receptor families in Cannabidiol's inhibitory impact on the acquisition and expression phases of methamphetamine (MET), the conditioned place preference (CPP) procedure as a common method to assay reward characteristics of drugs was carried out. Six groups of rats were treated by various doses of SCH23390 or Sulpiride (0.25, 1, and 4 µg/0.5 µL) in the NAc as D1 or D2 dopamine receptor family antagonists, respectively, prior to infusion of Cannabidiol (10 µg/5 µL) in the lateral ventricle (LV) over conditioning phase in the acquisition experiments. In the second step of the study, animals received SCH23390 or Sulpiride in the NAc before Cannabidiol (50 µg/5 µL) infusion into the LV in the expression phase of MET to illuminate the influence of SCH23390 or Sulpiride on the inhibitory impact of Cannabidiol on the expression of MET-induced CPP. Intra-NAc administration of either SCH23390 or Sulpiride impaired Cannabidiol's suppressive impact on the expression phase, while just Sulpiride could suppress the Cannabidiol's impact on the acquisition phase of the MET-induced CPP. Also, the inhibitory impact of Sulpiride was stranger in both phases of MET reward. It seems that Cannabidiol prevents the expression and acquisition phases of MET-induced CPP partly through the dopaminergic system in the NAc.

Precisely Fabricated Sulpiride-Loaded Nanolipospheres with Ameliorated Oral Bioavailability and Antidepressant Activity.

BACKGROUND: Sulpiride (SUL), is a selective antidopaminergic drug that had extensive biological activities. However, its sparingly aqueous solubility and limited gastrointestinal permeability lead to scanty oral bioavailability which hinders its clinical efficacy. OBJECTIVE: SUL-loaded lipospheres (SUL-LPS) were designed to serve as an oral biocompatible nanovector for improving SUL permeability as well as conquering its low oral absorption and then in turn enhancing its antidepressant action. METHODS: SUL-LPS were fabricated via two processing techniques namely, melt emulsification and solvent evaporation. The impact of different lipid cores, phospholipid shells together with various surfactant concentrations and types on the lipospheres properties were screened. Detailed physicochemical elucidations were performed followed by ex vivo permeation appraisal using the non-everted intestine model. The pharmacokinetic parameters of SUL-LPS, free SUL and marketed product were assessed following oral administration to healthy rats. Reserpine-induced depression rat model was used to assess the antidepressant action of SUL-LPS on which full behavioural and biochemical analysis was conducted. Safety attributes of nanoencapsulated SUL on the brain and other internal organs were evaluated. RESULTS: The optimum LPS revealed an excellent nanosize with a narrow PdI, negative zeta potential and acceptable entrapment efficiency of 68.62 nm, 0.242, -30.4 mV and 84.12%, respectively. SUL-LPS showed a sustained release pattern and 2.1-fold enhancement in the intestinal permeation parameters with low mucin interaction. Oral pharmacokinetic appraisal exhibited that LPS provided 3.4-fold improvement in SUL oral bioavailability together with long-circulating properties, relative to the free drug. Pharmacodynamic study confirmed the superior antidepressant action of SUL-LPS as evident by 1.6 and 1.25-fold elevation in the serotonin and dopamine expressions, respectively. Meanwhile, nanotoxicological appraisal proved the biocompatibility of SUL-LPS upon repetitive oral administration. CONCLUSION: Rationally designed lipospheres hold promising in vitro and in vivo characteristics for efficient delivery of SUL with high oral bioavailability, antidepressant activity together with a good safety profile.

Temporary inactivation of the infralimbic cortex impairs while the blockade of its dopamine D2 receptors enhances auditory fear extinction in rats.

Fear extinction is defined as decline in conditioned fear responses that occurs with repeated and non-reinforced exposure to a feared conditioned stimulus. Experimental evidence suggests that the extinction of fear memory requires the integration of the medial prefrontal cortex (mPFC); nevertheless, the role of its sub-regions in regulating the expression and extinction of auditory fear has been rarely addressed in literature. The present study examined the roles of the infra-limbic (IL) and pre-limbic (PL) regions of the mPFC in the expression and extinction of auditory fear by temporally deactivating these regions using lidocaine (10 µg/0.5 µl) before training male Wistar rats in auditory fear-conditioning tasks. The results showed increased freezing levels and impaired extinction through deactivating the IL rather than the PL cortex. Given the role of the dopaminergic pathways in regulating fear memory, this study also investigated the role of D2 receptors located in the IL cortex in fear extinction. Fear extinction was improved in an inverted U-shape pattern through the intra-IL infusion of 15.125, 31.25, 62.5, 125, 250 and 500 ng/0.5 µl of the D2 receptor antagonist sulpiride. In other words, the moderate doses, i.e. 31.25, 62.5, 125, 250 ng/0.5 µl, enhanced auditory fear extinction, whereas the lowest and highest doses, i.e. 15.125 and 500 ng/0.5 µl, were ineffective. These findings demonstrated the key roles of the IL cortex and its dopamine D2 receptors in regulating auditory fear in rats.

A novel nasal co-loaded loratadine and sulpiride nanoemulsion with improved downregulation of TNF-α, TGF-ß and IL-1 in rabbit models of ovalbumin-induced allergic rhinitis.

PURPOSE: The work aimed to develop a co-loaded loratadine and sulpiride nasal nanoemulsion for allergic rhinitis management. METHODS: Compatibility studies were conducted adopting differential scanning calorimetry and Fourier transform infrared spectroscopy. Nanoemulsion formulations were prepared using soybean lecithin, olive oil and tween 80. Sodium cholate and glycerol were employed as co-surfactants. Nanoemulsions were assessed for viscosity, pH, droplet size, polydispersity index, zeta potential, electrical conductivity, entrapment, In vitro drug release and corresponding kinetics. Stability of the selected formulation was investigated. The biological effectiveness was evaluated in rabbit models of ovalbumin-induced allergic rhinitis by measuring TNF-α, TGF-ß and IL-1. RESULTS: Compatibility studies revealed absence of drug/drug interactions. Nanoemulsions exhibited > 90% entrapment efficiency. The selected nanoemulsion demonstrated small droplet size (85.2 ± 0.2 nm), low PDI (0.35 ± 0.0) and appropriate Zeta Potential (-23.3 ± 0.2) and stability. It also displayed enhanced in vitro drug release following the Higuashi Diffusion and Baker-Lonsdale models. The mean relative mRNA expression of TNF-α, IL-1 and TGF-ß significantly decreased from 9.59 ± 1.06, 4.15 ± 0.02 and 4.15 ± 0.02 to 1.28 ± 0.02, 1.93 ± 0.06 and 1.56 ± 0.02 respectively after treatment with the selected nanoemulsion formulation. CONCLUSION: The results reflected a promising potent effect of the combined loratadine and sulpiride nasal nanoemulsion in managing the symptoms of allergic rhinitis.

Oral galactagogues (natural therapies or drugs) for increasing breast milk production in mothers of non-hospitalised term infants.

BACKGROUND: Many women express concern about their ability to produce enough milk, and insufficient milk is frequently cited as the reason for supplementation and early termination of breastfeeding. When addressing this concern, it is important first to consider the influence of maternal and neonatal health, infant suck, proper latch, and feeding frequency on milk production, and that steps be taken to correct or compensate for any contributing issues. Oral galactagogues are substances that stimulate milk production. They may be pharmacological or non-pharmacological (natural). Natural galactagogues are usually botanical or other food agents. The choice between pharmacological or natural galactagogues is often influenced by familiarity and local customs. Evidence for the possible benefits and harms of galactagogues is important for making an informed decision on their use. OBJECTIVES: To assess the effect of oral galactagogues for increasing milk production in non-hospitalised breastfeeding mother-term infant pairs. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), Health Research and Development Network - Phillippines (HERDIN), Natural Products Alert (Napralert), the personal reference collection of author LM, and reference lists of retrieved studies (4 November 2019). SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs (including published abstracts) comparing oral galactagogues with placebo, no treatment, or another oral galactagogue in mothers breastfeeding healthy term infants. We also included cluster-randomised trials but excluded cross-over trials. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. Two to four review authors independently selected the studies, assessed the risk of bias, extracted data for analysis and checked accuracy. Where necessary, we contacted the study authors for clarification. MAIN RESULTS: Forty-one RCTs involving 3005 mothers and 3006 infants from at least 17 countries met the inclusion criteria. Studies were conducted either in hospitals immediately postpartum or in the community. There was considerable variation in mothers, particularly in parity and whether or not they had lactation insufficiency. Infants' ages at commencement of the studies ranged from newborn to 6 months. The overall certainty of evidence was low to very low because of high risk of biases (mainly due to lack of blinding), substantial clinical and statistical heterogeneity, and imprecision of measurements. Pharmacological galactagogues Nine studies compared a pharmacological galactagogue (domperidone, metoclopramide, sulpiride, thyrotropin-releasing hormone) with placebo or no treatment. The primary outcome of proportion of mothers who continued breastfeeding at 3, 4 and 6 months was not reported. Only one study (metoclopramide) reported on the outcome of infant weight, finding little or no difference (mean difference (MD) 23.0 grams, 95% confidence interval (CI) -47.71 to 93.71; 1 study, 20 participants; low-certainty evidence). Three studies (metoclopramide, domperidone, sulpiride) reported on milk volume, finding pharmacological galactagogues may increase milk volume (MD 63.82 mL, 95% CI 25.91 to 101.72; I² = 34%; 3 studies, 151 participants; low-certainty evidence). Subgroup analysis indicates there may be increased milk volume with each drug, but with varying CIs. There was limited reporting of adverse effects, none of which could be meta-analysed. Where reported, they were limited to minor complaints, such as tiredness, nausea, headache and dry mouth (very low-certainty evidence). No adverse effects were reported for infants. Natural galactagogues Twenty-seven studies compared natural oral galactagogues (banana flower, fennel, fenugreek, ginger, ixbut, levant cotton, moringa, palm dates, pork knuckle, shatavari, silymarin, torbangun leaves or other natural mixtures) with placebo or no treatment. One study (Mother's Milk Tea) reported breastfeeding rates at six months with a concluding statement of "no significant difference" (no data and no measure of significance provided, 60 participants, very low-certainty evidence). Three studies (fennel, fenugreek, moringa, mixed botanical tea) reported infant weight but could not be meta-analysed due to substantial clinical and statistical heterogeneity (I2 = 60%, 275 participants, very low-certainty evidence). Subgroup analysis shows we are very uncertain whether fennel or fenugreek improves infant weight, whereas moringa and mixed botanical tea may increase infant weight compared to placebo. Thirteen studies (Bu Xue Sheng Ru, Chanbao, Cui Ru, banana flower, fenugreek, ginger, moringa, fenugreek, ginger and turmeric mix, ixbut, mixed botanical tea, Sheng Ru He Ji, silymarin, Xian Tong Ru, palm dates; 962 participants) reported on milk volume, but meta-analysis was not possible due to substantial heterogeneity (I2 = 99%). The subgroup analysis for each intervention suggested either benefit or little or no difference (very low-certainty evidence). There was limited reporting of adverse effects, none of which could be meta-analysed. Where reported, they were limited to minor complaints such as mothers with urine that smelled like maple syrup and urticaria in infants (very low-certainty evidence). Galactagogue versus galactagogue Eight studies (Chanbao; Bue Xue Sheng Ru, domperidone, moringa, fenugreek, palm dates, torbangun, moloco, Mu Er Wu You, Kun Yuan Tong Ru) compared one oral galactagogue with another. We were unable to perform meta-analysis because there was only one small study for each match-up, so we do not know if one galactagogue is better than another for any outcome. AUTHORS' CONCLUSIONS: Due to extremely limited, very low certainty evidence, we do not know whether galactagogues have any effect on proportion of mothers who continued breastfeeding at 3, 4 and 6 months. There is low-certainty evidence that pharmacological galactagogues may increase milk volume. There is some evidence from subgroup analyses that natural galactagogues may benefit infant weight and milk volume in mothers with healthy, term infants, but due to substantial heterogeneity of the studies, imprecision of measurements and incomplete reporting, we are very uncertain about the magnitude of the effect. We are also uncertain if one galactagogue performs better than another. With limited data on adverse effects, we are uncertain if there are any concerning adverse effects with any particular galactagogue; those reported were minor complaints. High-quality RCTs on the efficacy and safety of galactagogues are urgently needed. A set of core outcomes to standardise infant weight and milk volume measurement is also needed, as well as a strong basis for the dose and dosage form used.

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.

Sulpiride gastro-retentive floating microsponges; analytical study, in vitro optimization and in vivo characterization.

Sulpiride (SUL), anti-dopaminergic drug, has a specific site for absorption located in the upper portion of the gastrointestinal tract hence, its oral delivery represents a challenge regarding SUL absorption and bioavailability. So, a gastro-retentive oral platform of SUL was developed to increase its gastric residence time, release SUL at a controlled rate in the stomach and consequently, enable it to reach its specific absorption site. Floating microsponges were prepared via quasi-emulsion solvent diffusion method and characterised for their physico-chemical properties. In addition, Taguchi design of experiment was utilised to optimise some independent variables affecting microsponges performance. The optimised SUL microsponges showed a yield of 79.82 ± 2.37%, an encapsulation efficiency of 89.11 ± 2.28% and in vitro time for floatation of 8.0 h. Additionally, pharmacokinetics were investigated in rabbits and compared with the commercial SUL formulation, Dogmatil® capsules. Optimised SUL microsponges showed a significantly (p < .05) higher Cmax, AUC and 2-fold increase in oral bioavailability compared with the commercial product. Moreover, the optimised SUL microsponges remained present in the stomach up to 8.0 h post administration when viewed via X-ray radiographs in rabbits. It could be concluded that the floating microsponges could be useful as an oral platform to enhance the sulpiride absorption and bioavailability.

In silico Analysis of Sulpiride, Synthesis, Characterization and In vitro Studies of its Nanoparticle for the Treatment of Schizophrenia.

BACKGROUND: Sulpiride, which has selective dopaminergic blocking activity, is a substituted benzamide antipsychotic drug playing a prominent role in the treatment of schizophrenia, which more selective and primarily blocks dopamine D2 and D3 receptor. OBJECTIVE: This study has two main objectives, firstly; the molecular modeling studies (MD and Docking, ADME) were conducted to define the molecular profile of sulpiride and sulpiridereceptor interactions, another to synthesize polymeric nanoparticles with chitosan, having the advantage of slow/controlled drug release, to improve drug solubility and stability, to enhance utility and reduce toxicity. METHODS: Molecular dynamic simulation was carried out to determine the conformational change and stability (in water) of the drug and the binding profile of D3 dopamine receptor was determined by molecular docking calculations. The pharmacological properties of the drug were revealed by ADME analysis. The ionic gelation method was used to prepare sulpiride loaded chitosan nanoparticles (CS NPs). The Dynamic Light Scattering (DLS), UV-vis absorption (UV), Scanning Electron Microscopy (SEM), Fourier transform infrared (FT-IR) spectroscopy techniques were carried out to characterize the nanoparticles. In vitro cell cytotoxicity experiments examined with MTT assay on mouse fibroblast (L929), human neuroblastoma (SH-SY5Y) and glioblastoma cells (U-87). The statistical evaluations were produced by ANOVA. RESULTS: The residues (ASP-119, PHE-417) of D3 receptor provided a stable docking with the drug, and the important pharmacological values (blood brain barrier, Caco-2 permeability and human oral absorption) were also determined. The average particle size, PdI and zeta potential value of sulpiride- loaded chitosan NPs having a spherical morphology were calculated as 96.93 nm, 0.202 and +7.91 mV. The NPs with 92.8% encapsulation and 28% loading efficiency were found as a slow release profile with 38.49% at the end of the 10th day. Due to the formation of encapsulation, the prominent shifted wave numbers for C-O, S-O, S-N stretching, S-N-H bending of Sulpiride were also identified. Mitochondrial activity of U87, SHSY-5Y and L929 cell line were assayed and evaluated using the SPSS program. CONCLUSION: To provide more efficient use of Sulpiride having a low bioavailability of the gastrointestinal tract, the nanoparticle formulation with high solubility and bioavailability was designed and synthesized for the first time in this study for the treatment of schizophrenia. In addition to all pharmacological properties of drug, the dopamine blocking activity was also revealed. The toxic effect on different cell lines have also been interpreted.

Altered dopamine signalling in chronic epigastric pain syndrome.

Chronic epigastric pain syndrome (CEPS) is an important diagnostic problem, especially in patients without macroscopic and microscopic changes in gastric mucosa. The cause of this ailment is unclear. The aim of this study was the assessment of coexistence between symptoms of this syndrome and secretion level of dopamine (DA), as well as the efficacy of peripheral and central D2 receptors antagonist. Sixty depressive patients with CEPS occurring independently of the diet and with no Helicobacter pylori infection and 30 healthy subjects were enrolled in this study. Plasma DA and urinary homovanilic acid (HVA) concentration were measured by ELISA, and the mRNA expression of dopa decarboxylase (DDC) in gastric mucosa was evaluated by RT-PCR in 30 patients with CEPS and 30 controls. Severity of epigastric pain before and after 12 weeks 2 x 50 mg itopride or sulpiride treatment was evaluated using the modified 10-point Visual Analogue Scale. Higher average levels of plasma DA and urinary HVA levels in CEPS patients than controls 129.5 ± 22.0 versus 109.1 ± 18.4 pg/ml (p < 0.001) and 6.82 ± 1.55 versus 5.39 ± 1.04 mg/24 h, respectively were obtained. Moreover, the expression of DDC in gastric mucosa of CEPS patients was higher than in healthy subjects (p < 0.01). Sulpiride subsided epigastric pain in 73.3%, but itopride reduced it only in 6.6% of CEPS patients. We concluded that altered dopamine signalling may affect locally-and-centrally mediated chronic epigastric pain.

Effectiveness of Phenolic Antioxidants in Experimental Model of Benign Prostatic Hyperplasia.

Experimental model of sulpiride-provoked benign prostatic hyperplasia was employed to comparatively assess the effect of phenolic antioxidants (dihydroquercetin, p-thyrozol, dibornol, and prostagenin) on prostate morphology. All examined agents decreased the degree of hyperplasia in acinar epithelium; the greatest efficacy was demonstrated by prostagenin. Moreover, dihydroquercetin and p-thyrozol increased the cross-section area of acinar lumina and prostate volume, which is inadmissible in this pathology. These results suggest that the use of phenolic antioxidants in the therapy of benign prostatic hyperplasia should be strictly controlled.

Pharmacokinetics of levosulpiride after single-dose administration in goats (Capra hircus) by different routes of administration.

Levosulpiride (LSP) is the l-enantiomer of sulpiride, and LSP recently replacing sulpiride in several EU countries. Several studies about LSP in humans are present in the literature, but neither pharmacodynamic nor pharmacokinetic data of LSP is present for veterinary species. The aim of this study was to assess the pharmacokinetic profile of LSP after intravenous (IV), intramuscular (IM), and oral (PO) administration in goats. Animals (n = 6) were treated with 50 mg LSP by IV, IM, and PO routes according to a randomized cross-over design (3 × 3 Latin-square). Blood samples were collected prior and up to 24 hr after LSP administration and quantified using a validated HPLC method with fluorescence detection. IV and IM administration gave similar concentration versus time curve profiles. The IM mean bioavailability was 66.97%. After PO administration, the drug plasma concentrations were detectable only in the time range 1.5-4 hr, and the bioavailability (4.73%) was low. When the AUC was related to the administered dose in mg/kg, there was a good correlation in the IV and IM groups, but very low correlation for the PO route. In conclusion, the IM and IV administrations result in very similar plasma concentrations. Oral dosing of LSP in goats is probably not viable as its oral bioavailability was very low.

Development and characterisation of levosulpiride-loaded suppositories with improved bioavailability in vivo.

The purpose of this study was to develop and characterize levosulpiride loaded liquid suppository with improved bioavailability. The content of levosulpiride-loaded liquid suppositories were optimized in a series of experiments using various weight ratios of P188, P407, Tween 80, and drug. The suppositories were liquid at room temperature, however, when rectally administered, they became gel at body temperature. Their rheological properties and release characteristics were determined in vitro while pharmacokinetic study was performed after its rectal administration in rats and compared with drug suspension. Poloxamer 188 and Twee 80 decreased the gelation temperature and gelation time, but increased the gel strength and mucoadhesive force of liquid suppositories. Liquid suppository composed of [Levosulpiride/P 188/P 407/Tween 80 (1/15/17/3%)] with a gelation temperature of about 30.7 °C remained liquid at 25 °C, but converted to gel at 30-36.5 °C, resulting in easy administration and rapid gelation inside the body. This liquid suppository gave a considerably increased dissolution rate reflected in a meaningfully higher plasma concentration and 7.1-fold AUC values of levosulpiride in rats as compared to the drug suspension. Hence, liquid suppository system could be used for enhanced bioavailability of levosulpiride-loaded pharmaceutical products.

Amisulpride-CD-Loaded Liposomes: Optimization and In Vivo Evaluation.

Amisulpride (AMS) is an atypical antipsychotic agent used for the treatment of schizophrenia. The effect of different variables, i.e., the type of cyclodextrins (CDs), ratio of drug/CDs, and type of loading on the prepared AMS-CD liposomes (single and double loaded) was studied by applying 23 full factorial design. Double-loaded liposomes are loaded with AMS-hydroxyl propyl-ß-cyclodextrin (HP-ß-CD) in the aqueous phase and free drug in the lipophilic bilayer, while single-loaded liposomes are loaded only with AMS-HP-ß-CD in the aqueous phase. Entrapment efficiency, particle size, polydespersibility, and zeta potential were selected as dependent variables. Design Expert® software was used to obtain an optimized formulation with high entrapment efficiency (64.55 ± 1.27%), average particle size of 40.1 ± 2.77 nm, polydespersibility of 0.44 ± 0.37, and zeta potential of - 48.8 ± 0.28. Optimized formula was evaluated for in vitro release, surface morphology and stability study was also conducted. AMS-HP-ß-CD in double-loaded liposomes exhibited higher drug release than those in the conventional liposomes and in the single-loaded liposomes. The maximum plasma concentration (Cmax) of AMS in optimized AMS-HP-ß-CD double-loaded liposomal formulation increased by 1.55- and 1.29-fold, as compared to the commercial tablets and conventional liposomes, respectively. However, the relative bioavailability of AMS double-loaded liposomes was 1.94- and 1.28-folds of commercial tablet and conventional liposomes, respectively.

Dopaminergic Drug Effects on Probability Weighting during Risky Decision Making.

Dopamine has been associated with risky decision-making, as well as with pathological gambling, a behavioral addiction characterized by excessive risk-taking behavior. However, the specific mechanisms through which dopamine might act to foster risk-taking and pathological gambling remain elusive. Here we test the hypothesis that this might be achieved, in part, via modulation of subjective probability weighting during decision making. Human healthy controls (n = 21) and pathological gamblers (n = 16) played a decision-making task involving choices between sure monetary options and risky gambles both in the gain and loss domains. Each participant played the task twice, either under placebo or the dopamine D2/D3 receptor antagonist sulpiride, in a double-blind counterbalanced design. A prospect theory modelling approach was used to estimate subjective probability weighting and sensitivity to monetary outcomes. Consistent with prospect theory, we found that participants presented a distortion in the subjective weighting of probabilities, i.e., they overweighted low probabilities and underweighted moderate to high probabilities, both in the gain and loss domains. Compared with placebo, sulpiride attenuated this distortion in the gain domain. Across drugs, the groups did not differ in their probability weighting, although gamblers consistently underweighted losing probabilities in the placebo condition. Overall, our results reveal that dopamine D2/D3 receptor antagonism modulates the subjective weighting of probabilities in the gain domain, in the direction of more objective, economically rational decision making.

Pharmacotherapy for primary delusional jealousy, a retrospective observational study of 32 cases with Othello syndrome.

To determine whether primary delusional jealousy can be treated effectively with antipsychotics or antidepressants, and whether any clinical variables are associated with response to pharmacotherapy, we carried out a retrospective case series observational study by reviewing clinical records of patients with an International Classification of Disease, 9th ed., diagnostic code of 297 (delusional disorders) who were treated at the Department of Psychiatry of a university affiliated hospital from January 2010 to December 2015. Only those records showing obvious delusional jealousy not secondary to other medical conditions, dementia, or schizophrenia were scrutinized thoroughly with respect to types of pharmacotherapy, treatment response, and other demographic and clinical variables likely to be associated with clinical outcomes. All except one of 32 patients, 16 men and 16 women, between 37 and 79 (60.9±10.6) years of age, were treated with low-dose antipsychotics. The general response was favorable as 19 (59.4%) were rated as good and 13 as inadequate responders (seven partial and six limited). Compared with antipsychotic monotherapy, concomitant therapy with antidepressants had a higher rate of good response, although statistically insignificant (75 vs. 53%, P=0.21). Younger age (P=0.01) and presentation at the index visit with their suspected unfaithful spouse were associated with a good response (P=0.036); comorbidity with delusions other than the jealous type was associated with a poor response (P=0.006). The overall outcome for delusional jealousy looks promising if the patients can accept pharmacotherapy in an outpatient setting.

Monoaminergic neurotransmission is mediating the antidepressant-like effects of Passiflora edulis Sims fo. edulis.

The genus Passiflora is popularly used to treat anxiety. Recent studies showed antidepressant-like effects of two varieties of P. edulis (edulis and flavicarpa) in mice. However, the mechanisms of antidepressant actions are still unknown. Here, the effects of P. edulis fo. edulis aqueous extract (AE, 100-300mg/kg, po), and ethyl acetate (AcOEt, 25-50mg/kg, po), butanol (BuOH, 25-50mg/kg, po) and residual aqueous (25-100mg/kg, po) fractions were investigated in the mouse forced swimming test. In addition, the involvement of monoamines in the P. edulis fractions-induced antidepressant actions was approached. HPLC analyses showed that AcOEt and BuOH, but not residual, fractions shared with AE the main peaks between 25 and 70min (UV 340nm), which are suggestive of flavonoids. Nortriptyline and fluoxetine reduced the immobility time and similar results were observed for AE, AcOEt and BuOH but not residual fractions. PCPA (inhibitor of 5-HT synthesis), AMPT (inhibitor of catecholamine synthesis) and sulpiride (selective D2 receptor antagonist), but not DSP-4 (noradrenergic neurotoxin), blocked the antidepressant actions of AcOEt and BuOH. In conclusion, AcOEt and BuOH fractions shared with AE similar phytochemical composition and antidepressant actions. Preserved 5-HT and dopamine transmissions were required for the antidepressant effects of P. edulis fractions.

A Population Approach to Guide Amisulpride Dose Adjustments in Older Patients With Alzheimer's Disease.

OBJECTIVE: We have previously reported high dopamine D2/3 receptor occupancies at low amisulpride concentrations in older people with Alzheimer's disease (AD), during off-label treatment of AD-related psychosis. This post hoc analysis explored pharmacokinetic (concentration) and pharmacodynamic (prolactin, D2/3 occupancy) contributions to symptom reduction and extrapyramidal side effects (EPS) to inform AD-specific dose adjustments. METHODS: Population pharmacokinetic-pharmacodynamic models were developed by combining pharmacokinetic data from a phase 1 study in 20 healthy older people with pharmacokinetic prolactin, [¹8F]fallypride D2/3 receptor imaging, and clinical outcome data from 28 older patients prescribed open amisulpride (25-75 mg/d) to treat AD-related psychosis. Model predictions were used to simulate dose-response and dose-EPS. RESULTS: Symptom reduction (delusions) was associated with amisulpride concentration (P = 1.3e-05) and D2/3 occupancy (P < .01, caudate, putamen, thalamus). Model predictions suggested that across concentrations of 40-100 ng/mL, and occupancies of 40% to 70% in the caudate and thalamus and 30% to 60% in the putamen, there was a 50% to 90% probability of response and < 30% probability of EPS. Simulations, based on concentration-delusions and concentration-EPS model outputs, showed that 50 mg/d of amisulpride was the appropriate dose to achieve this target range in those aged > 75 years; increasing the dose to 75 mg/d increased the risk of EPS, particularly in those aged > 85 years of low body weight. CONCLUSIONS: These findings argue strongly for the consideration of age- and weight-based dose adjustments in older patients with AD-related psychosis and indicate that 50 mg/d of amisulpride may be both the minimal clinically effective dose and, in those aged > 75 years, the maximally tolerated dose.

Multiple organic cation transporters contribute to the renal transport of sulpiride.

Sulpiride, a selective dopamine D2 receptor blocker, is used widely for the treatment of schizophrenia, depression and gastric/duodenal ulcers. Because the great majority of sulpiride is positively charged at physiological pH 7.4, and ~70% of the dose recovered in urine is in the unchanged form after human intravenous administration of sulpiride, it is believed that transporters play an important role in the renal excretion of sulpiride. The aim of the present study was to explore which transporters contribute to the renal disposition of sulpiride. The results demonstrated that sulpiride was a substrate of human carnitine/organic cation transporter 1 (hOCTN1) and 2 (hOCTN2), human organic cation transporter 2 (hOCT2), human multidrug and toxin efflux extrusion protein 1 (hMATE1) and 2-K (hMATE2-K). Sulpiride accumulation from the basolateral (BL) to the apical (AP) side in MDCK-hOCT2/pcDNA3.1 cell monolayers was much greater than that in MDCK-hOCT2/hMATE1 cells, and cimetidine dramatically reduced the intracellular accumulation of sulpiride from BL to AP. In addition, the accumulation of sulpiride in mouse primary renal tubular cells (mPRTCs) was markedly reduced by inhibitors of Oct2 and Octns. The results implied that OCTN1, OCTN2, OCT2, MATE1 and MATE2-K probably contributed to the renal transfer of sulpiride, in which OCT2 mediated the uptake of sulpiride from the bloodstream to the proximal tubular cells, while MATEs contributed to the sulpiride efflux from the proximal tubular cells to the renal lumen, and OCTNs participated in both renal secretion and reabsorption.

The effects of l-DOPA and sulpiride on growth hormone secretion at different injection times in Holstein steers.

The effects of l-DOPA, a precursor of dopamine (DA), and sulpiride, a D2 -type DA receptor blocker, on growth hormone (GH) and prolactin (PRL) secretion were investigated in steers. Eight Holstein steers (212.8 ± 7.8 kg body weight) were used. Lighting conditions were 12:12 L:D (lights on: 06.00-18.00 hours). Blood samplings were performed during the daytime (11.00-15.00 hours) and nighttime (23.00-03.00 hours). Intravenous injections of drugs or saline were performed at 12.00 hour for the daytime and 00.00 hour for the nighttime, respectively. Plasma GH and PRL concentrations were determined by radioimmunoassay. l-DOPA did not alter the GH secretion when it was injected at 12.00 hour (spontaneous GH level at its peak). On the other hand, l-DOPA increased GH secretion at 00.00 hour (GH level at its trough). Injection of sulpiride suppressed GH secretion at 12.00 hour but did not affect GH levels at 00.00 hour. l-DOPA inhibited and sulpiride stimulated PRL release during both periods. These results suggest that dopaminergic neurons have stimulatory action on GH secretion and inhibitory action on PRL secretion in cattle. In addition, injection time should be considered to evaluate the exact effects on GH secretion due to its ultradian rhythm of GH secretion in cattle.

Pregnancy outcomes in women reporting ingestion of levosulpiride in early pregnancy.

This study aimed to evaluate pregnancy outcomes of women who were inadvertently exposed to levosulpiride in early pregnancy. All 162 consecutive singleton pregnant women counselled through the Korean Motherisk Program, Cheil General Hospital, between April 2001 and April 2014, on teratogenic risk after inadvertent exposure to levosulpiride in early pregnancy were enrolled in this study. The women were exposed to levosulpiride at median 4.8 gestational weeks. The rate of miscarriage was not significantly different between groups (9.2% in those exposed and 5.5% in the non-exposed; p = .084). The rate of major malformations was not significantly different between exposed (2.7%) and non-exposed pregnancies (4.4%) (p = .481). All other pregnancy outcomes between the two groups were comparable (p > .05). Our data suggest that levosulpiride causes no significant adverse effects on pregnancy outcomes and therefore may be not a major teratogen.