Dopamine Receptor Agonist Bromocriptine Research Articles

Uterine Notch2 facilitates pregnancy recognition and corpus luteum maintenance via upregulating decidual Prl8a2.

The maternal recognition of pregnancy is a necessary prerequisite for gestation maintenance through prolonging the corpus luteum lifespan and ensuring progesterone production. In addition to pituitary prolactin and placental lactogens, decidual derived prolactin family members have been presumed to possess luteotropic effect. However, there was a lack of convincing evidence to support this hypothesis. Here, we unveiled an essential role of uterine Notch2 in pregnancy recognition and corpus luteum maintenance. Uterine-specific deletion of Notch2 did not affect female fertility. Nevertheless, the expression of decidual Prl8a2, a member of the prolactin family, was downregulated due to Notch2 ablation. Subsequently, we interrupted pituitary prolactin function to determine the luteotropic role of the decidua by employing the lipopolysaccharide-induced prolactin resistance model, or blocking the prolactin signaling by prolactin receptor-Fc fusion protein, or repressing pituitary prolactin release by dopamine receptor agonist bromocriptine, and found that Notch2-deficient females were more sensitive to these stresses and ended up in pregnancy loss resulting from abnormal corpus luteum function and insufficient serum progesterone level. Overexpression of Prl8a2 in Notch2 knockout mice rescued lipopolysaccharide-induced abortion, highlighting its luteotropic function. Further investigation adopting Rbpj knockout and DNMAML overexpression mouse models along with chromatin immunoprecipitation assay and luciferase analysis confirmed that Prl8a2 was regulated by the canonical Notch signaling. Collectively, our findings demonstrated that decidual prolactin members, under the control of uterine Notch signaling, assisted pituitary prolactin to sustain corpus luteum function and serum progesterone level during post-implantation phase, which was conducive to pregnancy recognition and maintenance.

Precision weighting of cortical unsigned prediction error signals benefits learning, is mediated by dopamine, and is impaired in psychosis

Recent theories of cortical function construe the brain as performing hierarchical Bayesian inference. According to these theories, the precision of prediction errors plays a key role in learning and decision-making, is controlled by dopamine and contributes to the pathogenesis of psychosis. To test these hypotheses, we studied learning with variable outcome-precision in healthy individuals after dopaminergic modulation with a placebo, a dopamine receptor agonist bromocriptine or a dopamine receptor antagonist sulpiride (dopamine study n = 59) and in patients with early psychosis (psychosis study n = 74: 20 participants with first-episode psychosis, 30 healthy controls and 24 participants with at-risk mental state attenuated psychotic symptoms). Behavioural computational modelling indicated that precision weighting of prediction errors benefits learning in health and is impaired in psychosis. FMRI revealed coding of unsigned prediction errors, which signal surprise, relative to their precision in superior frontal cortex (replicated across studies, combined n = 133), which was perturbed by dopaminergic modulation, impaired in psychosis and associated with task performance and schizotypy (schizotypy correlation in 86 healthy volunteers). In contrast to our previous work, we did not observe significant precision-weighting of signed prediction errors, which signal valence, in the midbrain and ventral striatum in the healthy controls (or patients) in the psychosis study. We conclude that healthy people, but not patients with first-episode psychosis, take into account the precision of the environment when updating beliefs. Precision weighting of cortical prediction error signals is a key mechanism through which dopamine modulates inference and contributes to the pathogenesis of psychosis.

OATP1A2 and OATP2B1 Are Interacting with Dopamine-Receptor Agonists and Antagonists.

Interaction with the dopaminergic system in the central nervous system is either therapeutically intended or it is a side effect. In both cases, dopamine-receptor agonists (DRA) like the ergoline derivative bromocriptine and dopamine-receptor antagonists (DRAn) like metoclopramide have to cross the blood-brain barrier (BBB). The organic anion transporting polypeptides (OATP) 1A2 and 2B1 are cellular uptake carriers for a variety of endogenous and xenobiotic compounds. As both transporters are expressed in endothelial cells of the BBB, the aim of the present study was to determine whether the DRA bromocriptine, cabergoline, and pergolide and the DRAn metoclopramide and domperidone are interacting with OATP1A2 and 2B1 and could therefore be candidate genes modifying wanted and unwanted effects of these drugs. Localization of both transporters in the brain was confirmed using LC-MS/MS and immunofluorescence stainings. For the functional studies, MDCKII cells stably expressing OATP1A2 or 2B1 were used. Initial interaction studies with the well-characterized transporter substrate estrone 3-sulfate revealed that all tested compounds except pergolide inhibit the transport function of both proteins with the most potent effect for bromocriptine (IC50 = 2.2 μM (OATP1A2) and IC50 = 2.5 μM (OATP2B1)). Further studies using the indirect competitive counterflow method identified bromocriptine, cabergoline, and domperidone as substrates of both transporters, whereas metoclopramide was only transported by OATP1A2. These findings were verified for domperidone by direct measurements using its tritium-labeled form as a tracer. Moreover, the transporter-mediated uptake of this compound was sensitive to the OATP1A2 and OATP2B1 inhibitor naringin. In conclusion, this study suggests that OATP1A2 and 2B1 may play a role in the uptake of DR agonists and antagonists into the brain.

Особливості лікування хворих з артеріальною гіпертензією із супутнім ожирінням: невідоме про відоме

Introduction. Arterial Hypertension is the most common disease of the circulatory system. Today we can talk about it as a non-infectious epidemic. Obesity is a risk factor and a frequent comorbid condition in hypertension. The aim. Given the role of dopamine metabolism as one of the pathogenetic triggers of hypertension and obesity, to study the effect of a dopamine receptor agonist bromocriptine in this category of patients. Materials and methods. We examined 111 hypertensive patients with concomitant obesity and 18 hypertensive patients without obesity with dopamine (DA) metabolism disorders. 24 patients with concomitant obesity received the dopamine receptor agonist bromocriptine and the calcium antagonist amlodipine to correct their DA metabolism disorders. The level of DA was determined according to the daily excretion of DA in the urine by fluorometric method. Determination of angiotensin II (ATII) was performed using enzyme-linked immunosorbent assay. The concentration of lipids was determined using the enzymatic colorimetric method, blood pressure was assessed using Daily Monitoring of Blood Pressure (ABPM), the condition of the endothelium was determined using D.S Celermajer’s endothelium-dependent vasodilation assessment. Results. Concomitant obesity leads to a deeper impairment in the dopaminergic system, RAAS, lipid spectrum and endothelial status. Bromocriptine and amlodipine treatment resulted in a significant increase in urinary DA excretion by 1.77 times (77.4%) and a trend towards blood ATII increase, which confirms the assumption of similar mechanism of action of dopamine agonists and angiotensin II receptor antagonist; positivization of lipid spectrum parameters: significant reduction of total cholesterol by 5.7%, TG by 14.01%, LDL by 5.5%. Regarding other lipid metabolism, such as HDL, there was a trend towards increase by 4.6%, combined with a significant improvement in endothelium-dependent vasodilation by 54.8%, lower blood pressure and a positive modulating effect of the combination of these drugs on the daily blood pressure profile against the background of a significant decrease in body weight by 8.8%.

Mechanisms of the antidiabetic action of bromocriptine, dopamine receptor agonist, and experience of its use in type 2 diabetic patients in type 2 diabetic patients

Hyperactivation of the sympathetic nervous system plays an important role in the pathogenesis of metabolic syndrome and type 2 diabetes mellitus (T2D), and therefore the use of sympatholytic drugs is a promising. Dopamine receptor agonist bromocriptine exerts a modulating effect on metabolic control through central and peripheral effects. Objective — to evaluate the effectiveness of bromocriptine as monotherapy or in combination with metformin in the treatment of patients with T2D. Materials and methods. Patients with deco­m­pensated T2D (men, age 49.2 ± 4.15 years) were prescribed bromocriptine in addition to metformin therapy (n = 16, group 1) or as monotherapy after discontinuation of sulfonylureas (n = 6, group 2). Anthropometric parameters, indicators of carbohyd­rate and lipid metabolism, levels of C-peptide, cortisol, DHEA-S were determined. Results and discussion. After 6 months of treat­ment, level of HbA1c decreased in all patients by 0.5 % compared to the baseline (p < 0.05), without changing the concentration of C-peptide. Unchanged level of total testosterone and corticosteroids balance prove the absence of an effect on the function of the gonads and adrenal cortex. During treatment, there was no cases of hypoglycemia or changes in anthropometric parameters. Conclusions. Treatment with bromocriptine in combination with metformin improved the glycemic control and lipid profile of the blood, without excessive secretion of insulin and effect on body weight. In patients who had previously taken sulfonylureas with hypoglycemic events,bromocriptine as monotherapy ensured proper control of glycemia and triglycerides, without changing insulin secretion and new episodes of hypoglycemia, andwith concomitant normalization of prolactin.

Dopamine receptor agonist bromocriptine restrains the follicular development, hatchling success and puberty in Gambusia affinis

The present investigation was conducted to determine the influence of dopamine (DA) receptor agonist bromocriptine (BRO) on reproduction and onset of puberty in the viviparous fish Gambusia affinis. In the first experiment, the mean number of stage I and II follicles (previtellogenic) in 0.8 or 5 mg BRO treated fish did not show significant difference compared to those of experimental controls, whereas the mean number of stage III follicles were significantly lower in 5 mg BRO treated fish compared to experimental controls. However, treatment of 0.8 or 5 mg BRO resulted in significantly lower numbers of stage IV (early vitellogenic) and V (late vitellogenic) follicles compared to those of experimental controls. There was decrease in the percent occurrence of pregnancy and different stages of embryos in BRO treated fish compared with the experimental controls. Concomitant with this, sparsely distributed gonadotropin releasing hormone immunoreactive (GnRH-ir) fibres were observed in the proximal pars distalis (PPD) region of the pituitary gland in BRO treated fish compared to those of dense accumulations of these fibres in the PPD region of the pituitary gland in experimental controls. In the second experiment, exposure of juveniles (25 DPH) to same doses of BRO for 45 days resulted in complete absence of vitellogenic follicles and presence of few GnRH-ir fibres in 5 mg BRO treated juvenile in contrast to presence of vitellogenic follicles and dense aggregation of GnRH fibres in treatment controls. Overall, the results of the present investigation suggest that DA affects ovarian follicular and embryonic development and onset of puberty in viviparous species.

Monoaminergic modulation of decision-making under risk of punishment in a rat model.

The ability to decide advantageously among options that vary in both their risks and rewards is critical for survival and well-being. Previous work shows that some forms of risky decision-making are robustly modulated by monoamine signaling, but it is less clear how monoamine signaling modulates decision-making under risk of explicit punishment. The goal of these experiments was to determine how this form of decision-making is modulated by dopamine, serotonin, and norepinephrine signaling, using a task in which rats choose between a small, 'safe' food reward and a large food reward associated with variable risks of punishment. Preference for the large, risky reward (risk-taking) was reduced by administration of a D2/3 dopamine receptor agonist (bromocriptine) and a selective D2 agonist (sumanirole). The selective D3 agonist PD128907 appeared to attenuate reward discrimination abilities but did not affect risk-taking per se. In contrast, drugs targeting serotonergic and noradrenergic signaling had few if any effects on choice behavior. These data suggest that in contrast to other forms of risky decision-making, decision-making under risk of punishment is selectively modulated by dopamine signaling, predominantly through D2 receptors.

The therapeutic effect of bromocriptine in combination with spironolactone in patients with primary aldosteronism: a hypothesis generating pilot study.

BackgroundDopamine D2-like receptors are attenuated in aldosterone producing adenoma, lead to overproduction of aldosterone in affected patients, and thus reported to serve as a potential treatment target for primary aldosteronism. The D2 dopamine receptor agonist bromocriptine has been used clinically for reducing tumor mass of pituitary adenomas of lactotroph origin. The aim of the present study was to assess the efficacy of adding bromocriptine to spironolactone in the biochemical control of primary aldosteronism.MethodsThirty patients (15 aldosterone producing adenoma) received bromocriptine treatment with dose titration to a daily dose of 7.5mg. Urine aldosterone and potassium excretion ratio of all patients were compared based on the result of metoclopramide test at baseline.ResultsOn the basis of response to metoclopramide at baseline, the proportions of patients with lower urine aldosterone and urine potassium level after taking bromocriptine for six months were higher in the high metoclopramide response group. Initial aldosterone-renin ratio and high metoclopramide response at baseline were independent predictors of a decrease in aldosterone secretion after a six–month course of bromocriptine. The effects of bromocriptine added to spironolactone to reduce aldosterone secretion and potassium excretion in primary aldosteronism dissipated at 9 month after the initial treatment.ConclusionsIn this pilot study, we found that short-term addition of bromocriptine to spironolactone improved the biochemical control of primary aldosteronism. Dopamine agonist is more effective in patients with high baseline aldosterone-renin ratio and those sensitive to metoclopramide stimulation. However, this effect dissipated after 9 months.Clinical trial registry informationClinicalTrials. Gov number: NCT00451672; https://www.clinicaltrial.gov/ct2/show/NCT00451672?term=NCT00451672&rank =1; trial registry name: The Therapeutic Effect of Bromocriptin in Patients With Primary Aldosteronism.

Postaugmentation Galactocele Without Periareolar Incision and 8 Years After Pregnancy.

Sir: Galactocele is a rare breast augmentation complication. Addressing the risk factors involved, Harper et al1 found from previous galactocele reports that 100% of the implants were placed through periareolar incisions and 75% of patients either were on oral contraceptives at the time of their surgery or were lactating after pregnancy, with a remote history of augmentation mammaplasty. A recent retrospective study involving 832 patients and 3 (0.36%) cases of galactocele2 found that the use of a periareolar incision significantly increased the incidence of galactorrhea, but no mention toward increased risk of galactocele. We present a case of postaugmentation galactocele formation without periareolar incision and 8 years after her unique pregnancy. Our patient was a 26-year-old, gravida 1, para 0, abortus 1, without any significant medical or surgical history. She stopped oral contraceptives 30 days before and after surgery. An ultrasound scan showed 1 small (1.1 cm3) benign simple cyst in each breast. She underwent bilateral subglandular augmentation mammaplasty with 285 mL high-profile Silimed (Rio de Janeiro, Brazil) silicone gel implant and vertical, infra-areolar skin excess resection. She developed a painful enlargement of her left breast on postoperative day 17, without signs of inflammation or fever (Fig. ​(Fig.1).1). A postoperative ultrasound scan showed liquid collection around the implant but not suggestive of hematoma. A guided needle aspiration removed 89 mL of creamy fluid; the culture was negative for bacterial growth but biochemistry analyses concluded that it was breast milk. The patient was referred to a mastologist who started dopamine receptor agonist (bromocriptine), despite normal prolactin, for 2 weeks with no recurrence. Due to breast and implant pocket enlargement, the patient underwent revision surgery 6 months later to correct the left ptosis (Fig. ​(Fig.2)2) by skin resection, and the implant was moved to a dual plane pocket. The implant on the other side was also moved to the dual plane pocket due to breast symmetry. Fig. 1. Marked enlargement of the left breast at day 17 postoperatively. Fig. 2. Residual asymmetry due to left breast and implant pocket enlargement after galactocele’s treatment at 6 weeks postoperatively. Galactocele’s pathogenesis is still unknown, but obstruction of breast ducts associated with high levels of prolactin may play a significant role.3 Hyperprolactinemia may be due to intercostal nerve stimulation during surgery, leading to autonomic control over central neurogenic paths diminishing dopamine output into hypophysis’ portal circulation, increasing prolactin levels and milk secretion.4 Because our patient had none of the risk factors previously reported5 (periareolar incision, contraceptives intake, recent pregnancy or lactation, or hyperprolactinemia symptoms), we rely our etiopathogenesis hypothesis on duct obstruction because simple cysts were found preoperatively inside breast parenchyma. The treatment involved ultrasound-guided needle aspiration associated with dopamine agonist (bromocriptine) to halt hyperprolactinemia and milk production, which was successful with no recurrence. Other causes of hyperprolactinemia should be ruled out. Although it is rare, surgeons should be aware of this complication in augmentation mammaplasty. Considering the potential increased risk for galactocele, patients with previous thoracic or breast surgery, breast cysts, or spontaneous breast discharge should be assessed preoperatively for prolactin status to correct eventual disorders.

Dopaminergic modulation of distracter-resistance and prefrontal delay period signal.

Dopamine has long been implicated in the online maintenance of information across short delays. Specifically, dopamine has been proposed to modulate the strength of working memory representations in the face of intervening distracters. This hypothesis has not been tested in humans. We fill this gap using pharmacological neuroimaging. Healthy young subjects were scanned after intake of the dopamine receptor agonist bromocriptine or placebo (in a within-subject, counterbalanced, and double-blind design). During scanning, subjects performed a delayed match-to-sample task with face stimuli. A face or scene distracter was presented during the delay period (between the cue and the probe). Bromocriptine altered distracter-resistance, such that it impaired performance after face relative to scene distraction. Individual differences in the drug effect on distracter-resistance correlated negatively with drug effects on delay period signal in the prefrontal cortex, as well as on functional connectivity between the prefrontal cortex and the fusiform face area. These results provide evidence for the hypothesis that dopaminergic modulation of the prefrontal cortex alters resistance of working memory representations to distraction. Moreover, we show that the effects of dopamine on the distracter-resistance of these representations are accompanied by modulation of the functional strength of connections between the prefrontal cortex and stimulus-specific posterior cortex.

A well-refined in vitro model derived from human embryonic stem cell for screening phytochemicals with midbrain dopaminergic differentiation-boosting potential for improving Parkinson's disease.

Stimulation of endogenous neurogenesis is a potential approach to compensate for loss of dopaminergic neurons of substantia nigra compacta nigra (SNpc) in patients with Parkinson's disease (PD). This objective was to establish an in vitro model by differentiating pluripotent human embryonic stem cells (hESCs) into midbrain dopaminergic (mDA) neurons for screening phytochemicals with mDA neurogenesis-boosting potentials. Consequently, a five-stage differentiation process was developed. The derived cells expressed many mDA markers including tyrosine hydroxylase (TH), β-III tubulin, and dopamine transporter (DAT). The voltage-gated ion channels and dopamine release were also examined for verifying neuron function, and the dopamine receptor agonists bromocriptine and 7-hydroxy-2-(dipropylamino)tetralin (7-OH-DPAT) were used to validate our model. Then, several potential phytochemicals including green tea catechins and ginsenosides were tested using the model. Finally, ginsenoside Rb1 was identified as the most potent phytochemical which is capable of upregulating neurotrophin expression and inducing mDA differentiation.

Anterior ventral tegmental area dopaminergic neurons are not involved in the motivational effects of bromocriptine, pramipexole and cocaine in drug-free rats

Dopamine dysregulation syndrome in Parkinson's disease has been attributed to dopamine replacement therapies and/or a lesion of the dopaminergic system. Dopaminergic neuronal loss targets the substantia nigra and the ventral tegmental area (VTA). We hypothesize that dopamine replacement therapy is responsible for the potential reinforcement effect in Parkinson's disease, by acting on the neuronal reward circuitry. We previously demonstrated that the posterior (p) VTA, which projects to the nucleus accumbens (NAc), is implicated in the motivational effect of dopamine receptor agonists in 6-OHDA bilateral pVTA-lesioned drug-free animals. In the present study we investigated the implication of the anterior (a) VTA in the potential reinforcement effect of dopamine receptor agonists. Using the conditioned place preference (CPP) behavioral paradigm, we investigated the motivational effects of dopamine receptor agonists (bromocriptine and pramipexole), and cocaine in rats with a 6-OHDA bilateral lesion of the aVTA. Bromocriptine and pramipexole did not induce a significant CPP at 1mg/kg in both sham and bilateral 6-OHDA-lesioned rats. However bromocriptine induced CPP only at a dose of 3mg/kg in both animal groups. Moreover cocaine, which is known to increase dopamine release, induced reinforcing effects in both 6-OHDA-lesioned and sham rats. Our data show a lack of involvement of aVTA dopamine neurons in the motivational effects of bromocriptine, pramipexole and cocaine.

Anatomical connection strength predicts dopaminergic drug effects on fronto-striatal function

RationaleThe neurotransmitter dopamine plays a key role in cognitive functions that are associated with fronto-striatal circuitry and has been implicated in many neuropsychiatric disorders. However, there is a large variability in the direction and extent of dopaminergic drug effects across individuals.ObjectivesWe investigated whether individual differences in dopaminergic drug effects on human fronto-striatal functioning are associated with individual differences in white matter tracts.MethodsThe effects of the dopamine receptor agonist bromocriptine were assessed using functional magnetic resonance imaging in 22 healthy volunteers in a placebo-controlled, double-blind, within-subject design. Human psychopharmacology and functional neuroimaging were combined with functional connectivity analyses and structural connectivity analyses to establish a link between dopaminergic drug effects on fronto-striatal function and fronto-striatal anatomy.ResultsWe demonstrate that bromocriptine alters functional signals associated with attention switching in the basal ganglia. Crucially, individual differences in the drug’s effect on these signals could be predicted from individual differences in fronto-striato-thalamic white matter tracts, as indexed by diffusion tensor imaging. Anatomical fronto-striatal connectivity also predicted drug effects on switch-related functional connectivity between the basal ganglia and the prefrontal cortex.ConclusionsThese data reinforce the link between dopamine, cognition and the basal ganglia and have implications for the individual tailoring of dopaminergic drug therapy based on anatomical fronto-striatal connection strength.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-013-3000-5) contains supplementary material, which is available to authorized users.

1403 – Hyperprolactinemia and antipsychotic use in psychiatric patients

Hyperprolactinemia is a common, but neglected, adverse effect of conventional and some atypical antipshycotics, such as risperidone, paliperidone, amisulpride and zotepine, usually known as “prolactin-raising” antipshycotics. It occurs in almost 42% of men and in 75% of women with schizophrenia taking risperidone and involves prolactin levels greater than 210-420 mUI/L and 210-520 mUI/L, respectively. Atypical antipsychotics such as clozapine, quetiapine, olanzapine, aripiprazole and ziprazidone have a minimal or no significant effect in prolactin levels, being known as “prolactin-sparing” antipsychotics. This work aims to review the recent literature data concerning the management of the antipsychotic taking patients with hyperprolactinemia, regarding the clinical evaluation, differential diagnosis, therapeutic strategies and international recommendations. With the exception of the “Maudsley Prescribing Guidelines” and the “National Collaborating Centre for Mental Health”, none of the current international psychiatric guidelines recommend a routine baseline prolactin determination, neither periodic prolactin levels without the presence of any hyperprolactinemia symptoms. These symptoms include gynaecomastia, galactorrhoea, menstrual irregularities, infertility, sexual dysfunction, acne and hirsutism. Antipsychotic treatment is the most common cause of hyperprolactinemia in psychiatric patients, although it may also occur during the use of tricyclic and tetracyclic antidepressants, selective serotonin reuptake inhibitors and monoaminoxidase inhibitors, and in the presence of hyphotalamic and pituitary neoplasic disease. Antipsychotic-induced hyperprolactinemia therapeutic strategies may include antipsychotic dosage reduction, switching to a “prolactin-sparing” antipsychotic or using a dopamine receptor agonist (bromocriptine, cabergoline or amantadine). Given the osteopenic/ osteoporosis risk, combined oral contraceptives must be considered in women in fertile age with amenorrhoea for a year.

Parkinsonism in cirrhosis: pathogenesis and current therapeutic options

Acquired hepatolenticular degeneration, also known as "Parkinsonism in cirrhosis" is characterized by extrapyramidal symptoms including hypokinesia, dystonia and rigidity that are rapidly progressive and may be independent of the severity of cognitive dysfunction. Magnetic resonance imaging reveals T1-weighted hyperintense signals in both globus pallidus and substantia nigra. Estimates of the prevalence of Parkinsonism in cirrhosis have been reported as high as 21 %. The cause of Parkinsonism in cirrhosis has been attributed to manganese deposition in basal ganglia structures, leading to the dysfunction of the dopaminergic neurotransmitter system. In particular, there is evidence from both spectroscopic and biochemical investigations for damage to (or dysfunction of) presynaptic dopamine transporters together with a loss of post-synaptic dopamine receptors in basal ganglia of affected patients. Therapeutic options are limited; ammonia-lowering strategies are without substantial benefit, and an effective manganese chelator is not available. In many patients, L-Dopa replacement therapy and the dopamine receptor agonist bromocriptine are beneficial, and liver transplantation is generally effective. However, reports of post-transplant residual extrapyramidal symptoms suggest an element of irreversibility in some cases.

Human cognitive flexibility depends on dopamine D2 receptor signaling

RationaleAccumulating evidence indicates that the cognitive effects of dopamine depend on the subtype of dopamine receptor that is activated. In particular, recent work with animals as well as current theorizing has suggested that cognitive flexibility depends on dopamine D2 receptor signaling. However, there is no evidence for similar mechanisms in humans.ObjectivesWe aim to demonstrate that optimal dopamine D2 receptor signaling is critical for human cognitive flexibility.MethodsTo this end, a pharmacological pretreatment design was employed. This enabled us to investigate whether effects of the dopamine receptor agonist bromocriptine on task-set switching were abolished by pretreatment with the D2 receptor antagonist sulpiride. To account for individual (genetic) differences in baseline levels of dopamine, we made use of a common variable number of tandem repeat (VNTR) polymorphism in the 3′-untranslated region of the dopamine transporter gene, DAT1. ResultsBromocriptine improved cognitive flexibility relative to placebo, but only in subjects with genetically determined low levels of dopamine (n = 27). This beneficial effect of bromocriptine on cognitive flexibility was blocked by pretreatment with the selective dopamine D2 receptor antagonist sulpiride (n = 14).ConclusionsThese results provide strong evidence in favor of the hypothesis that human cognitive flexibility implicates dopamine D2 receptor signaling.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-011-2340-2) contains supplementary material, which is available to authorized users.

The D2 dopamine receptor agonist bromocriptine enhances voluntary but not involuntary spatial attention in humans

The D2 dopamine receptor agonist bromocriptine enhances voluntary but not involuntary spatial attention in humans

Evaluation of D2 and D3 dopamine receptor selective compounds on l-dopa-dependent abnormal involuntary movements in rats

A panel of novel D2 and D3 dopamine receptor selective antagonists, partial agonists and full agonists have been evaluated for the ability to attenuate l-dopa-associated abnormal involuntary movements (AIMs) in 6-hydroxydopamine (6-OHDA) unilaterally lesioned male Sprague Dawley rats, which is an animal model of l-dopa-induced dyskinesia (LID). LID is often observed in patients with Parkinson's Disease following chronic treatment with l-dopa. The intrinsic activity of these dopaminergic compounds was determined using a forskolin-dependent adenylyl cyclase inhibition assay with transfected HEK 293 cells expressing either the human D2Long or D3 dopamine receptor subtype. For the initial experiments the 5-HT1A receptor selective partial agonist buspirone was used to verify our ability to quantitate changes in total AIMs and AIMs minus locomotor scores. Two D2 dopamine receptor selective antagonists, SV 156 and SV 293, were evaluated and found to minimally attenuate AIM scores in these animals. Four members of our WC series of D3 dopamine receptor selective compounds of varying intrinsic activity at the D3 dopamine receptor subtype, WC 10, WC 21, WC 26 and WC 44, were also evaluated and found to attenuate AIM scores in a dose dependent manner. The in vivo efficacy of the compounds increased when they were administered simultaneously with l-dopa, as compared to when the compounds were administered 60 min prior to the l-dopa/benserazide. It was also found that the D3 receptor antagonist WC 10 could inhibit the involuntary movements after they had achieved maximum intensity. Unlike the D1-like dopamine receptor selective agonist SKF 81297 and the D2-like dopamine receptor agonist bromocriptine which can precipitate abnormal involuntary movements in these unilaterally lesioned animals, abnormal involuntary movements were not observed after administration of our D3 receptor selective agonist WC 44. In addition, we evaluated the effect of these four D3 dopamine receptor selective compounds for their effect on a) spontaneous locomotion and b) coordination and agility using a rotarod apparatus. We also used a cylinder test to assess the effect of l-dopa on spontaneous and independent use of each of the rat's forelimbs in the presence or absence of test compound. The results of these studies suggest that substituted phenylpiperazine D3 dopamine receptor selective compounds are potential pharmacotherapeutic agents for the treatment of l-dopa-associated dyskinesia in patients with Parkinson's Disease.

Protective effect of bromocriptine against BH4-induced Cath.a cell death involving up-regulation of antioxidant enzymes

Previously, we suggested that tetrahydrobiopterin (BH4), an obligatory cofactor for dopamine synthesis, as an intrinsic contributor to dopaminergic neuron vulnerability. The BH4 toxicity is observed in dopamine-producing cells, including Cath.a cells, but not in non-dopaminergic cells. Furthermore, the dopaminergic cell death induced by BH4 is apoptotic in nature and involves oxidative stress, similar to that observed in Parkinson's disease. Accordingly, various antioxidants have been found to protect dopaminergic cells from BH4. This study was undertaken to evaluate protective effects of the dopamine receptor agonist bromocriptine on BH4-induced Cath.a cell death, because bromocriptine has been reported to be an antioxidant with a neuroprotective activity. In the presence of bromocriptine, the increase in LDH activity and mitochondrial cytochrome c release induced by BH4 were significantly abolished. This cytoprotective effect was phosphatidylinositol 3-kinase (PI3K)/Akt pathway-dependent. In addition, bromocriptine was found to up-regulate the expressions of nuclear factor-E2-related factor-2 and antioxidant enzymes including NAD(P)H quinone oxidoreductase 1. Our findings show that bromocriptine stimulates antioxidant defense mechanisms in Cath.a cells and suggest a potential use of bromocriptine as a neuroprotectant.

D2 dopamine receptor-mediated antiproliferation in a small cell lung cancer cell line, NCI-H69

The D2 dopamine receptor agonist bromocriptine has been used clinically for reducing tumor mass of pituitary adenomas arising from lactotroph origins. As well, bromocriptine has been shown to have an antiproliferative effect on primary lactotrophs and lactotroph-derived cell lines. The presence of D2 dopamine-like receptors on NCI-H69 cells was previously established by the use of [(125)I]iodosulpride binding and has been confirmed in this study by use of reverse transcription PCR with receptor-specific primers. The reverse transcription PCR analysis of NCI-H69 cells demonstrates that both the D2s and D2l are expressed in NCI-H69 cells, with D2s having the higher relative expression. The activation of the D2R results in an inhibition of growth of NCI-H69 cells as assessed by the incorporation of [(3)H]thymidine; a process not sensitive to pertussis toxin. In NCI-H69 cells, the D2 dopamine-like receptor is coupled to the inhibition of forskolin-stimulated cAMP accumulation and to the stimulation of phospholipase D. The receptor-mediated inhibition of cAMP accumulation is ablated by overnight treatment with pertussis toxin but the stimulation of phospholipase D mediated by dopaminergic agonists is not. These data suggest that the phospholipase D pathway is responsible for the antiproliferative effects of D2 dopamine-like receptors agonists in small cell lung cancer cells. In support of this hypothesis, the inhibition of [(3)H]thymidine incorporation mediated by dopaminergic agonists was shown to be sensitive to the presence of ethanol. Taken together, these data suggest that the D2 dopamine-like receptor activates phospholipase D, which ultimately leads to an inhibition of growth of this small cell lung cancer cell line.