Metergoline Shares Properties with Atypical Antipsychotic Drugs Identified by Gene Expression Signature Screen.

Novel approaches are required to find new treatments for schizophrenia and other neuropsychiatric disorders. This study utilised a combination of in vitro transcriptomics and in silico analysis with the BROAD Institute's Connectivity Map to identify drugs that can be repurposed to treat psychiatric disorders. Human neuronal (NT2-N) cells were treated with a combination of atypical antipsychotic drugs commonly used to treat psychiatric disorders (such as schizophrenia, bipolar disorder, and major depressive disorder), and differential gene expression was analysed. Biological pathways with an increased gene expression included circadian rhythm and vascular endothelial growth factor signalling, while the adherens junction and cell cycle pathways were transcriptionally downregulated. The Connectivity Map (CMap) analysis screen highlighted drugs that affect global gene expression in a similar manner to these psychiatric disorder treatments, including several other antipsychotic drugs, confirming the utility of this approach. The CMap screen specifically identified metergoline, an ergot alkaloid currently used to treat seasonal affective disorder, as a drug of interest. In mice, metergoline dose-dependently reduced MK-801- or methamphetamine-induced locomotor hyperactivity confirming the potential of metergoline to treat positive symptoms of schizophrenia in an animal model. Metergoline had no effects on prepulse inhibition deficits induced by MK-801 or methamphetamine. Taken together, metergoline appears a promising drug for further studies to be repurposed as a treatment for schizophrenia and possibly other psychiatric disorders.

A macrophage-based screen identifies antibacterial compounds selective for intracellular Salmonella Typhimurium.

Salmonella Typhimurium (S. Tm) establishes systemic infection in susceptible hosts by evading the innate immune response and replicating within host phagocytes. Here, we sought to identify inhibitors of intracellular S. Tm replication by conducting parallel chemical screens against S. Tm growing in macrophage-mimicking media and within macrophages. We identify several compounds that inhibit Salmonella growth in the intracellular environment and in acidic, ion-limited media. We report on the antimicrobial activity of the psychoactive drug metergoline, which is specific against intracellular S. Tm. Screening an S. Tm deletion library in the presence of metergoline reveals hypersensitization of outer membrane mutants to metergoline activity. Metergoline disrupts the proton motive force at the bacterial cytoplasmic membrane and extends animal survival during a systemic S. Tm infection. This work highlights the predictive nature of intracellular screens for in vivo efficacy, and identifies metergoline as a novel antimicrobial active against Salmonella.

Anxiolytic effects of a semipurified constituent of guaraná seeds on rats in the elevated T-maze test.

The objective of this study was to investigate the effects of chronic administration of a semi-purified extract (Purified Extract A--PEA; 4, 8, or 16 mg/kg) of PAULLINIA CUPANA (guaraná) seeds on rats submitted to the elevated T-maze (ETM) model of generalized anxiety and panic disorders. The selective serotonin (5-HT) reuptake inhibitor (SSRI) paroxetine (PAR; 3 mg/kg), was used as a positive control. To evaluate possible serotonergic and dopaminergic neurotransmission involvement in the action of PEA during the ETM test, ineffective doses of metergoline (MET; 5-HT (2A/2C) antagonist receptor) or sulpiride (SUL; dopaminergic receptor antagonist) were acutely administered together with the PEA. The locomotion of the rats was assessed in a circular arena following each drug treatment. Both PEA (8 and 16 mg/kg) and PAR (3 mg/kg) increased one-way escape latencies from the open arm of the ETM, indicating a panicolytic effect compared to the control group. MET, in higher doses (1, 2 or 3 mg/kg), produced a panicolytic effect in the ETM test, whereas SUL did not (10, 20 or 40 mg/kg). The panicolytic effect produced by PEA (8 mg/kg) was blocked by both MET (2 mg/kg) and SUL (20 mg/kg), whereas the panicolytic effect produced by PAR (3 mg/kg) was blocked only by MET (2 mg/kg). These results show that chronic treatment with PEA produces a panicolytic effect during the ETM test, and that the dopaminergic and the serotonergic neurotransmission systems are involved in this effect.

Pharmacotherapy of seasonal affective disorder.

Seasonal affective disorder is a common variant of recurrent major depressive disorder or bipolar disorder. Treatment with bright artificial light has been found to be effective in this condition. However, for patients who do not respond to light therapy or those who lack compliance, conventional drug treatment with antidepressants also has been proposed. Substances with selective serotonergic or noradrenergic mechanisms should be preferred over older antidepressants. Although there are a number of open and controlled studies evaluating different compounds, these studies were often limited by relatively small sample sizes. Furthermore, there are no studies specifically addressing bipolar seasonal depression. This article will review the published literature on pharmacotherapy of seasonal affective disorder.

[Plasma prolactin concentration and the effect of metergoline in pseudopregnant Afghan hounds]. / Plasma-prolactineconcentraties en het effect van metergoline bij pseudogravide Afghaanse windhonden.

The effects of metergoline, a 5-hydroxytryptamine (serotinin) antagonist, on the plasma concentrations of prolactin in overtly pseudopregnant Afghan hounds and on the clinical symptoms of overt pseudopregnancy were studied. Plasma concentrations of prolactin and progesterone were determined in six Afghan hounds with signs of overt pseudopregnancy for 2-3 weeks and in three Afghan hounds that were not pseudopregnant at the time of blood sampling. In the overtly pseudopregnant bitches the plasma concentrations of prolactin before treatment (35.5 +/- 8.5 micrograms l-1) were significantly higher than the plasma concentrations of prolactin of the three bitches that were not pseudopregnant (6.3 +/- 0.5 micrograms l-1); the latter values were similar to those of non-psueodopregnant beagle bitches during the total luteal phase. The six pseudopregnant Afghan hounds were treated for 10 days with the antiserotoninergic drug metergoline. At 2 h after the onset of treatment with metergoline, the mean plasma concentration of prolactin had decreased to 10.8 +/- 2.9 micrograms l-1. The plasma concentrations of prolactin continued to decline to 5.4 +/- 1.0 micrograms l-1 at 4 h and to 1.0 +/- 0.1 microgram l-1 during treatment days 3-10. Signs of pseudopregnancy, such as swelling of the mammary glands and digging, decreased during the treatment period. The treatment was associated with mild behavioural side effects such as whimpering and aggressiveness. These side effects are probably not related to suppression of prolactin but are due to a direct effect on serotoninergic pathways in the brain. It is concluded that high plasma concentrations of prolactin are associated with the development and maintenance of pseudopregnancy. The serotonin antagonist metergoline strongly suppresses plasma concentration of prolactine in pseudopregnant dogs and decreases the clinical signs of pseudopregnancy.

Plasma concentrations of prolactin in overtly pseudopregnant Afghan hounds and the effect of metergoline.

The effect of metergoline, a 5-hydroxytryptamine (serotonin) antagonist, on the plasma concentrations of prolactin in overtly pseudopregnant Afghan hounds and on the clinical symptoms of overt pseudopregnancy were studied. Plasma concentrations of prolactin and progesterone were determined in six Afghan hounds with signs of overt pseudopregnancy for 2-3 weeks and in three Afghan hounds that were not pseudopregnant at the time of blood sampling. In the overtly pseudopregnant bitches the plasma concentrations of prolactin before treatment (35.5 +/- 8.5 micrograms l-1) were significantly higher than the plasma concentrations of prolactin of the three bitches that were not pseudopregnant (6.3 +/- 0.5 micrograms l-1); the latter values were similar to those of non-pseudopregnant beagle bitches during the total luteal phase. The six pseudopregnant Afghan hounds were treated for 10 days with the antiserotoninergic drug metergoline. At 2 h after the onset of treatment with metergoline, the mean plasma concentration of prolactin had decreased to 10.8 +/- 2.9 micrograms l-1. The plasma concentrations of prolactin continued to decline to 5.4 +/- 1.0 micrograms l-1 at 4 h and to 1.0 +/- 0.1 microgram l-1 during treatment days 3-10. Signs of pseudopregnancy, such as swelling of the mammary glands and digging, decreased during the treatment period. The treatment was associated with mild behavioural side effects such as whimpering and aggressiveness. These side effects are probably not related to suppression of prolactin but are due to a direct effect on serotoninergic pathways in the brain. It is concluded that high plasma concentrations of prolactin are associated with the development and maintenance of pseudopregnancy. The serotonin antagonist metergoline strongly suppresses plasma concentrations of prolactin in pseudopregnant dogs and decreases the clinical signs of pseudopregnancy.

The pharmacology of impulsive behaviour in rats: the effects of drugs on response choice with varying delays of reinforcement.

Impulsive behaviour is an important component of many psychiatric syndromes. It is often expressed as aggressive or violent behaviour, but may also be non-violent. One important factor which might lead to aggression or violence is an inability to tolerate a delay of gratification, leading to frustration and aggressive outbursts. In animals and in man, tolerance to delay of gratification can be studied using delay of reinforcement (also known as self-control) procedures. Experiments with delay of reinforcement in rats show that serotonergic mechanisms may be involved in this form of impulsive behaviour, which seems to support clinical findings in this area. The present experiment examined the effects of a series of psychoactive drugs on delays of reinforcement using a steady state operant procedure involving lever-pressing by rats. Rats were trained to choose between one food pellet delivered immediately and three or five pellets delivered after varying delays which increased during the course of the session. Using this procedure the rats remained sensitive to within-and between-session variations in delay of reinforcement even after long periods of testing. It was used to demonstrate an increase in impulsivity (after d-amphetamine) and a reduction in impulsivity (after diazepam and metergoline), indicated by shifts in the choice/delay function. The other drugs tested, imipramine, citalopram, haloperidol and carbamazepine, had no consistent effects although tested at doses which are active in other procedures. This method has proved to be a useful way of examining the effects of drugs on choice of delay of reinforcement in the rat. Although the behavioural basis of tolerance to delay of reinforcement (self-control) has received considerable attention, little is yet known about the biological basis. The present data indicate that the procedure described here can be used to elucidate the pharmacological basis of this aspect of impulsive behaviour.

[The treatment of pseudopregnancy in the bitch with prolactin inhibitors metergoline and bromocriptine]. / Untersuchung zur Behandlung der Scheinträchtigkeit der Hündin mit den Prolaktinhemmern Metergolin und Bromocryptin.

In the present study, the prolactin inhibitor Metergoline was compared with Bromocriptine and tested against a placebo in 63 pseudogravid bitches. Bromocriptine has already been tested successfully in numerous investigations on the therapy of canine pseudogravidity, but--probably because of its high price and vomitus as a frequent side effect--it has not been really introduced as a therapeutical device in canine practice. It can be deduced from the results presented herein that prolactin is essential for maintaining the pseudogravidity, but keeping up the lactation process--especially galactopoiesis--can probably not be ascribed solely to prolactin. However, prolactin definitely plays an essential role in the hormonal scenario, the detailed regulating mechanisms of which are not known until today. Thus, no statistically convincing therapy outcome could be achieved by the prolactin inhibitors compared to the placebo group. A tendency towards earlier regression of the symptoms "mammogenesis", "behavioural change" and "galactorrhea" was however present in the treated animals. A striking difference was the much more lively behaviour of the bitches with 53% being more lively in the Metergoline group, 37% in the Bromocriptine and 10% in the placebo group. There were also clear differences in the compatibility of the drugs; in the Bromocriptine group, 30% of the animals vomited, in the Metergoline only 6.3%. This however did not lead to termination of the therapy in any case. In two cases of the Metergoline group (6.3%), the medication was ended due to extreme restlessness.

[Use of lysenyl-forte and methergoline in the therapy of hyperprolactinemic hypogonadism]. / Primenenie lisenila-forte i metergolina v lechenii giperprolaktinemicheskogo gipogonadizma.

The paper is concerned with a study of the effectiveness of lysenyl-forte (Hemapol, Czechoslovakia) and methergoline (Carlo Erba, Italy) for therapy of patients with different types of hyperprolactinemic hypogonadism. Altogether 49 patients were investigated, of them 33 received lysenyl-forte at a dose of 0.6 mg/day and 16-methergoline at a dose of 12 mg/day for 3 months. A degree of galactorrhea, a menstrual cycle and the blood level of prolactin were assessed before and after therapy. A prolactin inhibiting effect of both drugs comparable with that of bromocriptine was noted. However a clinical effect and good tolerance were more frequently observed in this sampling in lysenyl therapy.

[Use of metergoline in the treatment of infertility associated with hyperprolactinemia]. / Opyt primeneniia metergolina v lechenii besplodiia, obuslovlennogo giperprolaktinemiei.

The usage of metergoline in patients with infertility and different forms (hinds) of hyperprolactinaemia was studied for 90 days at a dose of 12 mg. It gives a possibility to stimulate ovulation in 64% of patients and gain pregnancy in 8% of patients. In order to exceed the percentage of inpregnantion the course of medicine can be enlarged up to 6 months.

Arabinogalactan- and dextran-induced ear inflammation in mice: differential inhibition by H1-antihistamines, 5-HT-serotonin antagonists and lipoxygenase blockers.

Intravenous injection of arabinogalactan or dextran together with pontamine sky-blue dye into mice increased vascular permeability and led to marked blueing of the ears. Arabinogalactan caused a rapidly progressing ear blueing (maximal coloration 20-30 min after injection). This response was suppressed by pretreating the animals with the histamine H1-antihistamines levocabastine and loratadine. In contrast, dextran induced a slowly evolving ear inflammation (maximal coloration 60-90 min after injection), which was blocked by the 5-HT-serotonin antagonists cinanserin, metergoline and ritanserin. Furthermore, the dextran reaction was inhibited by the lipoxygenase (LO)/cyclooxygenase (CO) inhibitors BW540C, BW755C and phenidone and by the specific 5-LO inhibitor AA-861. Both arabinogalactan and dextran responses were inhibited by aprotinin, a kallikrein inhibitor, and the mixed H1/5-HT antagonists astemizole and azatadine. The inflammogenic activity of the polysaccharides was not affected by administration of the CO inhibitors indomethacin and suprofen, the thromboxane synthetase inhibitor dazoxiben, the H2-antihistamines cimetidine and ranitidine, the anticholinergics isopropamide or the PAF-antagonist L-652, 731. These data indicate the existence of distinctive endogenous molecules that mediate the pinnal extravasation reaction to both polysaccharides: histamine for arabinogalactan, serotonin and lipoxygenase-derived arachidonic acid metabolites for dextran.

[Effect of methergoline on impulse secretion of gonadotropins in women with hyperprolactinemic ovarian insufficiency]. / Vliianie metergolina na impu'lsnuiu sekretsiiu gonadotropinov u zhenshchin s giperprolaktinemicheskoi nedostatochnos'tiu iaichnikov.

The impact of methergoline, a serotonin antagonist, on the levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), prolactin, estradiol and progesterone was studied in the blood serum of 20 females with hyperprolactinemia-induced ovarian insufficiency who were under a ten-day course of its administration in a dose of 4-12 mg/day. Two patients were studied for gonadotrophin impulse secretion before and during methergoline treatment. It was revealed that the administration of the preparation led to a significant elevation of serum FSH and LH, estradiol and progesterone levels (up to the values characteristic of the preovulation phase) and enhancement of LH impulse secretion by the pituitary body. The possibility of dominant follicle growth and development was stated in the presence of persistent hyperprolactinemia. The authors supposed that the agent's effect was gained due to an enhanced secretion of the gonadotrophin-releasing hormone by the hypothalamus.

Animal model of anxiety: effect of metergoline in the genetically hypertensive rats of Koletsky type and in the rats of Wistar strain.

The experiments were carried out in the adult normotensive rats of Wistar strain and in the genetically hypertensive rats of Koletsky type; both sexes were used. The behavior in control and in druged animals was traced in new environment, in holeboard and in elevated plus-maze. In the control animals, when compared to the normotensive rats of Wistar strain, the genetically hypertensive rats of both sexes show elevated neophobia, reduced rate habituation of exploratory activity; the males of the latter strain then show reduced rate of rearing in holeboard and elevated aversion towards open space and hight in the elevated plus-maze. Metergoline at the dose 8 mg/kg b.w. normalized the rate of habituation of exploratory activity, reduced the aversion towards the open space and hight in elevated plus-maze in the genetically hypertensive rats of both sexes in the first session, in the males of normotensive rats in the second session. Moreover, Metergoline elevated directed exploration in the normotensive males and in both sexes of the genetically hypertensive rats and elevated rearing in the males of the genetically hypertensive rats. It can be concluded that Metergoline represents a potential anxiolytic drug.

Metergoline as an inhibitor of prolactin release.

In a randomized, double-blind study, 12 and 16 mg of metergoline and 5 mg of bromoergocriptine were given daily to three groups of 100 women each for ten consecutive days to prevent lactation. Excellent or good results were obtained in 86%, 90% and 83%, respectively. Serum prolactin (PRL) levels were evaluated in three settings. The first was after a single dose in four groups of patients (4, 6 and 8 mg of metergoline and 2.5 mg of bromoergocriptine were studied for ten hours). Second, for a study of the suckling reflex, PRL levels were measured 15, 30 and 60 minutes after breast stimulation in four groups of five patients each: two groups on the fourth postpartum day with and without metergoline treatment and two groups on the eighth postpartum day (the reflex was suppressed in the two groups treated with metergoline). Third, serum PRL levels rose after the intravenous administration of 200 mg of thyrotropin-releasing hormone (TRH) in another two groups of ten patients, one treated with metergoline and the other not so treated. TRH stimulation was not blocked in the treated groups.

[Metergoline in hyperprolactinemic breast cancer: a phase II study]. / Metergolin beim hyperprolaktinämischen Mammakarzinom: Eine Phase-II-Studie.

The prolactin release inhibiting action of the dopamine receptor agonist metergoline was investigated in 16 patients with metastatic breast cancer associated with hyperprolactinemia. At a daily dose of 12 mg p.o. for 30 days, the drug was highly effective in lowering prolactin levels (day 0: 1076 +/- 171, day 29: 249 +/- 46 mU/l) in these patients. Starting treatment with 4 mg/day, the side effects of the treatment were mild, including dizziness and nausea.

Treatment of hyperprolactinemic amenorrhea with Metergoline.

The ergoline derivative, Metergoline, in a dosage of 4 to 24 mg/day, was administered for one to eight months to 42 patients with hyperprolactinemic amenorrhea. Mean serum prolactin (PRL) concentrations before treatment were 91.2 ng/mL in the patients with functional hyperprolactinemia (N = 29) and 256.9 ng/mL in the patients with pituitary tumor (N = 13). Within four weeks, Metergoline treatment reduced these PRL concentrations to 39.5 ng/mL and 82.9 ng/mL, respectively. In this study Metergoline treatment resulted in restoration of menstruation in a total of 37 patients; 28 patients ovulated, and eight became pregnant. It is considerably more effective in functional hyperprolactinemia than in hyperprolactinemia caused by adenoma.