ergoline and Disease-Models--Animal

Cabergoline is an ergot-derived dopamine agonist used in the treatment of Parkinson's disease (PD). Both ergot and non-ergot-derived dopamine agonists directly stimulate dopamine receptors, unlike levodopa, which must undergo presynaptic breakdown to dopamine beforehand. Cabergoline has the longest half-life of the dopamine agonists currently available and is effective when given once-daily. It has been proposed that therapy with cabergoline may mimic physiological dopaminergic stimulation in PD by providing striatal intrasynaptic dopamine replacement. Its long half-life is likely to result in sustained rather than pulsatile dopaminergic stimulation, the preferred manner of treating PD. Placebo-controlled trials using cabergoline as an adjunctive therapy in PD have shown that it significantly reduces 'off' time, improves motor function and reduces levodopa requirements. Cabergoline has been shown to be as effective as other dopamine agonists in improving motor function as monotherapy in early PD, and a 5-year levodopa-controlled study indicates the superiority of cabergoline over levodopa in reducing dyskinesias. The efficacy of cabergoline in PD patients with nocturnal disabilities, restless leg syndrome and augmentation has also been demonstrated. Audits of the clinical efficacy of cabergoline indicate that it is well-tolerated and has an acceptable side effect profile.

Topics: Antiparkinson Agents; Cabergoline; Disease Models, Animal; Dopamine Agonists; Ergolines; Humans; Movement Disorders; Neuroprotective Agents; Parkinson Disease

The ability of MPTP to induce persistent parkinsonism in man may provide a vital clue to the cause of the idiopathic disease. However, the peripheral administration of MPTP to rodent species only produces losses in brain dopamine content and damage to the nigrostriatal system in high doses and no persistent motor deficits have been observed. In contrast, in primates, the administration of MPTP rapidly induces a persistent parkinsonian syndrome accompanied by evidence for selective damage to the nigro-striatal dopamine containing system. Other neurotransmitter systems appear unaffected by MPTP treatment. The MPTP-treated primate responds to the administration of L-DOPA and other antiparkinsonian drugs and may provide a useful test-bed for the development of novel antiparkinsonian medication. Administration of MPTP to primates causes an accumulation of MPP+ in a variety of brain areas. The accumulation of MPP+ and the neurotoxic actions of MPTP in primates can be prevented by the prior administration of monoamine oxidase inhibitors. The ability of monoamine oxidase inhibitors to prevent MPTP toxicity is related to the metabolism of MPTP by monoamine oxidase B, probably extraneuronally in glia, to produce MPDP+ and subsequently MPP+. In rodent synaptosomal preparations MPP+ is a substrate for the dopamine uptake mechanism and so would be selectively accumulated in brain dopamine neurones. Administration of MPTP to animals results in the production of a partial model of idiopathic Parkinson's disease as it occurs in man. MPTP treatment produces the major symptoms of Parkinson's disease in primates but the pathology is limited to the nigro-striatal system, whereas in Parkinson's disease pathology is more widespread. Biochemical changes induced by MPTP again seem primarily limited to those induced by damage to the nigro-striatal dopamine containing system. MPP+ (or another metabolite of MPTP) may be responsible for the neurotoxicity of MPTP but not all neurones which accumulate products of MPTP metabolism are damaged. The nigro-striatal system may be peculiarly sensitive to the effects of MPTP.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Benzazepines; Callithrix; Corpus Striatum; Disease Models, Animal; Dopamine; Ergolines; Humans; Levodopa; Macaca mulatta; Neural Pathways; Pargyline; Parkinson Disease; Parkinson Disease, Secondary; Pyridines; Quinpirole; Rats; Saimiri; Selegiline; Species Specificity; Substantia Nigra

The aim of this study is to investigate the effects of resveratrol in a rat model of ovarian hyperstimulation syndrome (OHSS) and compare with cabergoline.. Randomized controlled, animal study.. Female Wistar rats.. A rat OHSS model was used to investigate the effects of resveratrol compare with cabergoline administration for preventing OHSS. Body weight, ovary weight, diameter, vascular permeability (VP), vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2) expression (immunohistochemistry), and serum estradiol (E2) levels were then compared.. The ovarian VEGF concentration was significantly increased in the OHSS Groups (Groups 3-5) compared with the control groups (1 and 2). But vascular permeability, VEGF, and COX-2 expressions were reduced in animals treated with the resveratrol group compared with the cabergoline group (group 5) and the severe OHSS (group 3) group. Blood E2 levels were decreased in group treated with the resveratrol group compared with the cabergoline group (group 5) and severe the OHSS (group 3) group.. Our results in a rat model suggest that resveratrol has a beneficial effect on OHSS by reducing the increases in ovarian daimeter, VP, and VEGF expression associated with OHSS. These effects may be mediated by the COX-2 inhibitory capacity of resveratrol.

Topics: Animals; Antioxidants; Cabergoline; Disease Models, Animal; Dopamine Agonists; Ergolines; Female; Ovarian Hyperstimulation Syndrome; Ovary; Random Allocation; Rats; Rats, Wistar; Resveratrol; Stilbenes

To determine the effect of dopamine agonists in a surgically induced endometriosis model on rats.. In this prospective randomized experimental study, surgical induction of endometriosis was performed by autotransplantation technique on 52 adult female Wistar-Albino rats. Endometriosis formation was confirmed by a second-look laparotomy (n:48) 1 month later. Four study groups were randomly generated according to their treatment regimens: group 1 (leuprolide acetate, n = 12), group 2 (bromocriptine, n = 12), group 3 (cabergoline, n = 12) and group 4 (control, n = 12). Endometriotic implants were excised for histopathological examination after treatment at the setting of laparotomy. The mean surface areas and histopathological glandular tissue (GT) and stromal tissue (ST) scores of endometriotic implants were studied and compared among groups.. After 30 days of treatment, the mean surface area of the endometriotic implants of leuprolide acetate, bromocriptine and cabergoline groups was significantly decreased. The regression of endometriotic foci size in comparison to control was highest in group 1, followed by group 2, then group 3. In the histopathological evaluation both the ST and GT scores of group 1, 2 and 3 were significantly decreased in comparison to controls without a statistically significant difference between the groups.. Dopamine agonists are as effective as GnRH agonists in the regression of experimental endometriotic implants in rats. Further trials are needed to elucidate the pathways affected by dopamine agonists.

Topics: Adult; Animals; Antineoplastic Agents; Bromocriptine; Cabergoline; Disease Models, Animal; Dopamine Agonists; Endometriosis; Endometrium; Ergolines; Female; Gonadotropin-Releasing Hormone; Humans; Laparotomy; Leuprolide; Prospective Studies; Random Allocation; Rats; Rats, Wistar; Triptorelin Pamoate

VEGF-induced vascular permeability and blood vessels remodeling are key features of inflammatory bowel disease (IBD) pathogenesis. Dopamine through D2 receptor (D2R) inhibits VEGF/VPF-mediated vascular permeability and angiogenesis in tumor models. In this study, we tested the hypothesis that pathogenesis of IBD is characterized by the disturbance of dopaminergic system and D2R activity.. IL-10 knockout (KO) mice and rats with iodoacetamide-induced ulcerative colitis (UC) were treated intragastrically with D2R agonists quinpirole (1 mg/100 g) or cabergoline (1 or 5 µg/100 g). Macroscopic, histologic, and clinical features of IBD, colonic vascular permeability, and angiogenesis were examined.. Although colonic D2R protein increased, levels of tyrosine hydroxylase and dopamine transporter DAT decreased in both models of IBD. Treatment with quinpirole decreased the size of colonic lesions in rats with iodoacetamide-induced UC (p < 0.01) and reduced colon wet weight in IL-10 KO mice (p < 0.05). Quinpirole decreased colonic vascular permeability (p < 0.001) via downregulation of c-Src and Akt phosphorylation. Cabergoline (5 µg/100 g) reduced vascular permeability but did not affect angiogenesis and improved signs of iodoacetamide-induced UC in rats (p < 0.05).. Treatment with D2R agonists decreased the severity of UC in two animal models, in part, by attenuation of enhanced vascular permeability and prevention of excessive vascular leakage. Hence, the impairment dopaminergic system seems to be a feature of IBD pathogenesis.

Topics: Animals; Biopsy, Needle; Blotting, Western; Cabergoline; Capillary Permeability; Colitis, Ulcerative; Disease Models, Animal; Dopamine; Ergolines; Female; Humans; Immunohistochemistry; Inflammation Mediators; Inflammatory Bowel Diseases; Interleukin-10; Iodoacetamide; Mice; Mice, Inbred C57BL; Mice, Knockout; Quinpirole; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Statistics, Nonparametric

To determine the efficacy of montelukast in comparison with cabergoline in the prevention of ovarian hyperstimulation syndrome (OHSS) in rats.. An experimental OHSS model was formed in 35 female Wistar rats. Rats (22 days old) were randomized into 5 groups, each containing 7 animals. The control group received no therapy; the mild OHSS group was administered pregnant mare serum gonadotropin (PMSG) 10 IU for 4 days, hCG 10 IU on the 5th day; the severe OHSS group received PMSG 10 IU for 4 days, hCG 30 IU on the 5th day The montelukast group: received montelukast 10 mg/kg/day and the cabergoline group was administered cabergollne 100 microg/kg/day via oral gavage for 6 days (days 22-27), in addition to those of severe OHSS. All groups were sacrificed on 28th day Body weight, ovarian diameter and weight, vascular permeability vascular endothelial growth factor (VEGF), semiquantitative VEGF receptor-1, and VEGF receptor-2 (VEGFR-2) immunohistochemistry were evaluated.. Ovarian diameter and VEGF expression were significantly lower in the montelukast and cabergoline groups than in the severe OHSS group. While montelukast was more effective in limiting vascular permeability in the severe OHSS, cabergoline was superior to montelukast with respect to the limiting effect on increased body weight and VEGFR-2 expression.. The VEGF/VEGFR-2 interaction plays an important role in OHSS pathogenesis. Montelukast limits VEGF expression, and cabergoline reduces both VEGF and VEGFR-2 expressions; they are both effective therapies for the prevention of severe OHSS.

Topics: Acetates; Animals; Cabergoline; Chorionic Gonadotropin; Cyclopropanes; Disease Models, Animal; Dose-Response Relationship, Drug; Ergolines; Female; Ovarian Hyperstimulation Syndrome; Ovary; Quinolines; Random Allocation; Rats; Rats, Wistar; Sulfides

Although 6-hydroxydopamine-induced (6-OHDA-induced) rats are a well-known Parkinson's disease model, the effects of dopamine D2 agonists in mice with 6-OHDA-induced lesions are not completely understood. We produced mice with 6-OHDA-induced lesions and measured their total locomotion counts following administration of several dopamine D2 agonists (pramipexole, ropinirole, cabergoline, rotigotine, apomorphine, talipexole, and quinelorane). Cabergoline showed the longest duration of drug action, which was in agreement with its long-lived anti-Parkinson effects in rats and humans. In contrast, pramipexole and ropinirole had notably short durations of drug action. We demonstrated that mice with 6-OHDA-induced lesions accompanied with significant lesions in the striatum may be reasonable models to predict the action duration of anti-Parkinson drug candidates in humans.

Topics: Animals; Antiparkinson Agents; Apomorphine; Azepines; Benzothiazoles; Cabergoline; Corpus Striatum; Disease Models, Animal; Dopamine Agonists; Ergolines; Indoles; Injections, Intraventricular; Male; Mice; Motor Activity; Oxidopamine; Parkinsonian Disorders; Pramipexole; Quinolines; Receptors, Dopamine D2; Tetrahydronaphthalenes; Thiophenes

The dysfunction of immune regulation plays a critical role in the pathogenesis of a number of chronic inflammatory disorders, such as IBD. A close relationship between psychological stress and intestinal inflammation has been noted; the underlying mechanism remains elusive. This study aims to elucidate a pathological pathway between psychological stress and the dysfunction of regulatory T cells (Treg), and its effect on facilitating intestinal inflammation.. A restraint stress model was employed to induce psychological stress in mice. The functions of Tregs were determined by assessing the immune suppressor effects in the intestine. A mouse model of intestinal inflammation was established using a low dose of trinitrobenzene sulfonic acid (TNBS) or dextran sulfate sodium (DSS) together with the challenge of chronic stress.. After treating mice with restraint stress, the suppressor function of intestinal Treg was compromised, although the frequency of Treg was not changed in the intestine. Further observation revealed that stress induced Tregs in the intestine to differentiate into foxhead box P3(+) interleukin (IL)-17(+) tumour necrosis factor (TNF)-α(+) T cells. We also observed that exposure to stress-derived prolactin induced dendritic cells (DC) to produce IL-6 and IL-23 in vitro and in vivo, which played a critical role in altering Treg's phenotypes. Treating mice with chronic stress facilitated the initiation of intestinal inflammation by a low dose of TNBS or DSS, which was abolished by pretreatment with an inhibitor of prolactin, the cabergoline.. Psychological stress-derived prolactin alters DC and Treg's properties to contribute to intestinal inflammation.

Topics: Animals; Cabergoline; Colitis; Dextran Sulfate; Disease Models, Animal; Dopamine Agonists; Ergolines; Forkhead Transcription Factors; Immunity, Mucosal; Inflammation; Interleukins; Mice; Mice, Inbred BALB C; Prolactin; Stress, Psychological; T-Lymphocytes, Regulatory; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha

The anatomical factors involved in upper airway closure of obstructive sleep apnea (OSA) have been established. However, the mechanisms of repetitive OSA are not well understood. We found that dorsomedial medullary 5-HT2 receptor activity is compensated for by hypercapnia and elicits the immediate onset of poikilocapnic hypoxic ventilatory airway responses. Therefore, the aim of this study was to test the hypothesis that hypercapnia compensates for the immediate onset of poikilocapnic hypoxic ventilatory airway responses induced by dorsomedial medullary 5-HT2 receptors. Adult male mice (C57BL/6N) were intraperitoneally anesthetized with pentobarbital sodium. Microdialysis probes were inserted into the dorsomedial medulla oblongata of the mice. The mice were placed in a double-chamber plethysmograph and were allowed to acclimatize and recover from anesthesia. Mice were then exposed to hypercapnic hypoxic gases (7 % O2/5 % CO2 in N2) with or without 5-HT2-antagonist (10(-5) M LY-53857) perfusion. Respiratory curves through the head and body chambers were recorded to measure ventilatory airway variables. Extracellular fluid was collected every 5 min for HPLC analysis of 5-HT concentration. Hypercapnic hypoxia elicited neither delayed onset of ventilatory augmentation nor immediate airway narrowing with dorsomedial medullary 5-HT2 antagonism. Hypoxic polypnea was shifted downward. The increases in dorsomedial medullary 5-HT release and ventilatory volume were not affected with or without 5-HT2 activity. In conclusion, the onset of poikilocapnic hypoxic ventilatory airway responses mediated via dorsomedial medullary 5-HT2 activity is compensated for by hypercapnia. Maintenance of PCO2 level and CO2 responsiveness, especially with lowered 5-HT2 activity, may be important for preventing repetitive OSA.

Topics: Animals; Disease Models, Animal; Ergolines; Hypercapnia; Hypoxia; Male; Medulla Oblongata; Mice; Mice, Inbred C57BL; Receptors, Serotonin, 5-HT2; Serotonin; Serotonin Antagonists

The aim of this study is to investigate the effects of bevacizumab in a rat model of ovarian hyperstimulation syndrome (OHSS) and compare with cabergoline. The study was performed with 24 rats in four main groups (one non-stimulated control and three OHSS treatment groups; bevacizumab, cabergoline and placebo). The rats were randomly assigned to four experimental groups (six rats per group). Efficacy of treatment was assessed on 29th day by measuring weight gain, number of eggs, presence of ascites and ovarian weight. Peritoneal fluid levels of vascular endothelial growth factor (VEGF) were measured using an enzyme-linked immunosorbent assay. Ovarian weights were significantly higher in the OHSS groups than the control group. Ovarian weights in OHSS placebo group were found to be higher than those in OHSS-treatment groups (p = 0.002). VEGF levels were found increased in the OHSS-placebo group compared with the control group (p < 0.05). This increase was not seen in the OHSS groups treated with either bevacizumab or cabergoline. We demonstrate in this study that bevacizumab can lower VEGF production and ovarian weight in rats treated with gonadotropins.

Topics: Animals; Antibodies, Monoclonal, Humanized; Bevacizumab; Cabergoline; Cell Count; Disease Models, Animal; Drug Evaluation, Preclinical; Ergolines; Female; Organ Size; Ovarian Hyperstimulation Syndrome; Ovary; Ovum; Rats; Rats, Wistar

To determine the effect of non-selective 5-HT2C antagonist mesulergine and 5-HT2C agonist mCPP (metachlorophenylpiperazine) on learning acquisition (LA), short-term memory (STM) and long-term memory (LTM).. Experimental study.. Department of Biochemistry, University of Karachi, from December 2009 to June 2010.. Twenty-four male albino Wistar rats were used in this study. The agonist and antagonist (mCPP and mesulergine) were injected intraperitoneally at a dose 3.0 mg/kg in volumes of 1 ml/kg. Control animals were injected with saline (1 ml/kg). Animals were randomly divided into four groups (n=6). 1st being control group, 2nd being mCPP injected group, 3rd being mesulergine injected group and 4th group being injected with both mesulergine and mCPP. Behavioural activities of rats were monitored after 30 minutes of injection. For assessment of memory functions, water maze apparatus was used.. Administration of mCPP impaired STM, LTM and LA of rats. Mesulergine injected rats exhibited no alteration in memory functions. However, when it was injected with mCPP then there were no memory deficits induced by mCPP.. Ability of 5-HT2C receptor antagonist mesulergine to block the memory impairment effect of mCPP indicated an important regulatory role of 5-HT2C receptors in cognitive processes.

Topics: Analysis of Variance; Animals; Behavior, Animal; Disease Models, Animal; Ergolines; Male; Maze Learning; Memory Disorders; Memory, Long-Term; Memory, Short-Term; Piperazines; Random Allocation; Rats; Rats, Wistar; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists

To investigate the effect of antiangiogenic treatment on experimental endometriotic lesion nerve fibers.. Heterologous mouse model of endometriosis.. University Institute IVI, University Hospital La Fe.. Ovariectomized nude mice (n = 16) receiving human endometrial fragments from oocyte donors (n = 4).. Endometrium fragments stuck in the peritoneum of 5-week-old female nude mice treated with vehicle (n = 8) and antiangiogenic agent cabergoline (n = 8; Cb(2,) 0.05 mg/kg/day) for 14 days.. Immunofluorescence analysis of von-Willebrand factor (vWF) and vascular smooth muscle cells (αSMA) for evaluating the number of immature blood vessels (IBV) and microvascular density (MVD); immunochemical analysis of protein-gene product 9.5 (PGP 9.5) to assess nerve fibers density (NFD), and blue toluidine staining to confirm presence of mast cells and macrophages in endometriotic lesions.. All the results were quantified by morphometric techniques. The IBV, NFD, and number of macrophages and mast cells were statistically significantly decreased in the Cb2-treated group when compared with controls.. Antiangiogenic treatment statistically significantly diminishes new blood vessel formation after macrophage, mast cell, and nerve fiber reduction, providing a rationale to test antiangiogenic agents as a novel therapeutic approach to severe pelvic pain associated with human peritoneal endometriosis.

Topics: Actins; Angiogenesis Inhibitors; Animals; Biomarkers; Cabergoline; Disease Models, Animal; Endometriosis; Endometrium; Ergolines; Female; Fluorescent Antibody Technique; Humans; Immunohistochemistry; Macrophages; Mast Cells; Mice; Mice, Nude; Microvessels; Neovascularization, Pathologic; Nerve Fibers; Ovariectomy; Peritoneal Diseases; Time Factors; von Willebrand Factor

Female infertility is often associated with deregulation of hormonal networks, and hyperprolactinemia is one of the most common endocrine disorders of the hypothalamic-pituitary axis affecting the reproductive functions. We have shown previously that transgenic female mice overexpressing human chorionic gonadotropin β-subunit (hCGβ+ mice), and producing elevated levels of bioactive LH/hCG, exhibit increased production of testosterone and progesterone, are overweight and infertile, and develop hyperprolactinemia associated with pituitary lactotrope adenomas in adult age. In the present study, we analyzed the influence of the hyperprolactinemia of hCGβ+ females on their reproductive phenotype by treating them with the dopamine agonists, bromocriptine and cabergoline. Long-term bromocriptine treatment of adult mice was effective in the control of obesity, pituitary growth, and disturbances in the hormone profile, demonstrating that hyperprolactinemia was the main cause of the hCGβ+ female phenotype. Interestingly, short-term treatment (1 wk) with cabergoline applied on 5-wk-old mice corrected hyperprolactinemia, hyperandrogenism, and hyperprogesteronemia, prevented pituitary overgrowth, normalized gonadal function, and recovered fertility of adult hCGβ+ females after hormone-induced and natural ovulation. The same cabergoline treatment in the short term applied on 3-month-old hCGβ+ females failed to recover their reproductive function. Hence, we demonstrated that the short-term cabergoline treatment applied at a critical early stage of the phenotype progression effectively prevented the hyperprolactinemia-associated reproductive dysfunction of hCG-overproducing females.

Topics: Animals; Bromocriptine; Cabergoline; Chorionic Gonadotropin; Disease Models, Animal; Ergolines; Female; Fertility; Gene Expression Regulation; Humans; Hyperprolactinemia; Infertility; Mice; Mice, Transgenic; Ovulation; Phenotype; Time Factors

CXCL10 is one of the key chemokines involved in trafficking of autoaggressive T cells to the islets of Langerhans during the autoimmune destruction of beta cells in type 1 diabetes (T1D). Blockade of CXCL10 or genetic deletion of its receptor CXCR3 results in a reduction of T1D in animal models. As an alternative to the use of neutralizing monoclonal antibodies to CXCL10 or CXCR3 we evaluated the small molecule CXCR3 antagonist NIBR2130 in a virus-induced mouse model for T1D. We found that the overall frequency of T1D was not reduced in mice administered with NIBR2130. An initial slight delay of diabetes onset was not stable over time, because the mice turned diabetic upon removal of the antagonist. Accordingly, no significant differences were found in the islet infiltration rate and the frequency and activity of islet antigen-specific T cells between protected mice administered with NIBR2130 and control mice. Our data indicate that in contrast to direct inhibition of CXCL10, blockade of CXCR3 with the small molecule antagonist NIBR2130 has no impact on trafficking and/or activation of autoaggressive T cells and is not sufficient to prevent T1D.

Topics: Animals; Blood Glucose; CD8-Positive T-Lymphocytes; Cell Movement; Chemokine CXCL10; Diabetes Mellitus, Type 1; Disease Models, Animal; Ergolines; Glucose Tolerance Test; Insulin; Insulin-Secreting Cells; Interferon-gamma; Islets of Langerhans; Lymph Nodes; Lymphocytes; Lymphocytic choriomeningitis virus; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptors, CXCR3; Spleen; Th1 Cells; Viral Proteins

Implantation of a retrogradely shed endometrium during menstruation requires an adequate blood supply, which allows the growth of endometriotic lesions. This suggests that the development of endometriosis can be impaired by inhibiting angiogenesis. The growth of endometriotic foci is impaired by commercial oncological antiangiogenic drugs used to block vascular endothelial growth factor (VEGF) signaling. The dopamine agonist cabergoline (Cb2) inhibits the growth of established endometriosis lesions by exerting antiangiogenic effects through VEGFR2 inactivation. However, the use of ergot-derived Cb2 is associated with an increased incidence of cardiac valve regurgitation. To evaluate the potential usage of non-ergot-derived dopamine agonists for the treatment of human endometriosis, we compared the efficacy of quinagolide with that of Cb2 in preventing angiogenesis and vascularization in a heterologous mouse model of endometriosis. Nude mice whose peritoneum had been implanted with eutopic human endometrial fragments were treated with vehicle, 50  μg/kg per day oral Cb2, or 50 or 200  μg/kg per day quinagolide during a 14-day period. At the end of the treatment period, the implants were excised in order to assess lesion size, cell proliferation, degree of vascularization, and angiogenic gene expression. Neoangiogenesis was inhibited and the size of active endometriotic lesions, cellular proliferation index, and angiogenic gene expression were significantly reduced by both dopamine agonists when compared with the placebo. Given that Cb2 and quinagolide were equally effective in inhibiting angiogenesis and reducing lesion size, these experiments provide the rationale for pilot studies to explore the use of non-ergot-derived dopamine agonists for the treatment of endometriosis in humans.

Topics: Animals; Blood Vessels; Cabergoline; Cell Count; Cell Proliferation; Claviceps; Disease Models, Animal; Dopamine Agonists; Endometriosis; Endometrium; Ergolines; Female; Humans; Mice; Neovascularization, Pathologic; Receptors, Dopamine D2; Uterine Diseases; Vascular Endothelial Growth Factor Receptor-2

L-Dopa treatment, the gold standard therapy for Parkinson's disease, is hampered by motor complications such as dyskinesias. Recently, impairment of striatal Akt/GSK3 signaling was proposed to play a role in the mechanisms implicated in development of L-Dopa-induced dyskinesias in a rodent model of Parkinson's disease. The present experiment investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys, the effects on Akt/GSK3 of chronic L-Dopa treatment inducing dyskinesias compared to L-Dopa with CI-1041 (NMDA receptor antagonist) or a low dose of cabergoline (dopamine D2 receptor agonist) preventing dyskinesias. The extensive dopamine denervation induced by MPTP was associated with a decrease by about half of phosphorylated Akt(Ser473) levels in posterior caudate nucleus, anterior and posterior putamen; smaller changes were observed for phosphorylated Akt(Thr308) levels that did not reach statistical significance. Dopamine depletion reduced phosphorylated GSK3beta(Ser9) levels, mainly in posterior putamen whereas pGSK3beta(Tyr216) and pGSK3alpha(Ser21) were unchanged. In posterior caudate nucleus, anterior and posterior putamen of dyskinetic L-Dopa-treated MPTP monkeys, pAkt(Ser473) and pGSK3beta(Ser9) were elevated whereas L-Dopa+cabergoline treated MPTP monkeys without dyskinesias had lower values in posterior striatum as vehicle-treated MPTP monkeys. In non-dyskinetic MPTP monkeys treated with L-Dopa+CI-1041, putamen pAkt(Ser473) and pGSK3beta(Ser9) levels remained elevated as in dyskinetic monkeys while in posterior caudate nucleus, these levels were low as vehicle-treated and lower than L-Dopa treated MPTP monkeys. Extent of phosphorylation of Akt and GSK3beta in putamen correlated positively with dyskinesias scores of MPTP monkeys; these correlations were higher with dopaminergic drugs (L-Dopa, cabergoline) suggesting implication of additional mechanisms and/or signaling molecules in the NMDA antagonist antidyskinetic effect. In conclusion, our results showed that in MPTP monkeys, loss of striatal dopamine decreased Akt/GSK3 signaling and that increased phosphorylation of Akt and GSK3beta was associated with L-Dopa-induced dyskinesias.

Topics: Animals; Antiparkinson Agents; Benzoxazoles; Cabergoline; Corpus Striatum; Disease Models, Animal; Drug Interactions; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Ergolines; Female; Glycogen Synthase Kinase 3; Levodopa; Macaca fascicularis; Oncogene Protein v-akt; Parkinsonian Disorders; Phosphorylation; Piperidines; Serine; Signal Transduction; Statistics as Topic

To compare the efficacy of cabergoline (Cb2) and meloxicam in curbing vascular endothelial growth factor (VEGF) expression and preventing ovarian hyperstimulation syndrome (OHSS).. Randomized controlled, animal study.. Academic facility.. We used a total of 50 immature Wistar female rats randomly to create an experimental OHSS model.. Ten rats each formed the control group and mild OHSS group. The remaining 30 were separated into three equal groups of severe OHSS. Mild and severe OHSS were induced through ovarian stimulation with gonadotropins. One group with severe OHSS was administered a low-dose 100 microg/kg Cb2 therapy; another group with severe OHSS received 600 microg/kg meloxicam. Body weight, vascular permeability (VP), VEGF expression, ovary weight, and diameter were then compared.. The efficacy of Cb2 and meloxicam for preventing OHSS.. Comparison of the severe OHSS groups with the controls and mild OHSS group revealed significant increases in VEGF expression, VP, ovary weight, and diameter. The increase in VEGF expression was demonstrated to be dependent on human chorionic gonadotropin doses. However, low-dose Cb2 and meloxicam therapies were shown to be ineffective in decreasing VEGF expression and VP, ovary weight, and ovary diameter in severe OHSS.. VEGF elevation played a critical part in OHSS pathogenesis, but the therapies administered failed to curb VEGF expression.

Topics: Analysis of Variance; Animals; Biopsy, Needle; Body Weight; Cabergoline; Chorionic Gonadotropin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Ergolines; Female; Immunohistochemistry; Injections, Intramuscular; Meloxicam; Organ Size; Ovarian Hyperstimulation Syndrome; Ovary; Ovulation Induction; Pregnancy; Pregnancy, Animal; Probability; Random Allocation; Rats; Rats, Wistar; Thiazines; Thiazoles; Vascular Endothelial Growth Factor A

Dopamine agonists have been implicated in the treatment of depression. Cabergoline is an ergot derivative with a high affinity to dopamine D(2)-like receptors; however, there have been few preclinical studies on its antidepressant-like effects.. Behavioral effects of cabergoline were examined in rats using forced swimming (FST), novelty-suppressed feeding (NST), open field (OFT), and elevated-plus maze (EPT) tests. In a single treatment paradigm, behaviors of rats were analyzed 4 h after single injection of cabergoline (s.c., 0-4 micromol/kg). In a repeated-treatment paradigm, OFT, EPT, and FST were conducted on days 11, 12, and 13-14, respectively, during daily cabergoline injections (s.c., 0.5 micromol/kg), and then hippocampus was removed 24 h after the last injection. NST was conducted in a separate experiment at day 14. Western blotting was used for the analysis of the protein levels of brain-derived neurotrophic factor (BDNF) and the activation of intracellular signaling molecules.. Single injection of cabergoline demonstrated decreased immobility in FST and distance traveled during 0-10 min in OFT, while time spent and entry into open arms were increased at 4 micromol/kg. When cabergoline was repeatedly administered, immobility in FST and the latency of feeding in NSF were significantly reduced, while vertical movement was increased in OFT. The time in closed arms was tended to be decreased in EPT. Expression of BDNF and activation of extracellular signal-regulated kinase 1 were up-regulated after the chronic administration of cabergoline.. Cabergoline exerts antidepressant- and anxiolytic-like effects, which may be mediated by potentiation of intracellular signaling of BDNF.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Brain-Derived Neurotrophic Factor; Cabergoline; Depression; Disease Models, Animal; Dopamine Agonists; Dose-Response Relationship, Drug; Ergolines; Fluvoxamine; Hippocampus; Male; Mitogen-Activated Protein Kinase 3; Rats; Rats, Inbred WKY; Rats, Wistar; Signal Transduction; Up-Regulation

The aims of the current studies were to determine the in vitro and in vivo ocular and non-ocular pharmacological properties of cabergoline using well documented receptor binding, cell-based functional assays, and in vivo models. Cabergoline bound to native and/or human cloned serotonin-2A/B/C (5HT(2A/B/C)), 5HT(1A), 5HT(7), alpha(2B), and dopamine-2/3 (D(2/3)) receptor subtypes with nanomolar affinity. Cabergoline was an agonist at human recombinant 5HT(2), 5HT(1A) and D(2/3) receptors but an antagonist at 5HT(7) and alpha(2) receptors. In primary human ciliary muscle (h-CM) and trabecular meshwork (h-TM) cells, cabergoline stimulated phosphoinositide (PI) hydrolysis (EC(50)=19+/-7 nM in TM; 76 nM in h-CM) and intracellular Ca(2+) ([Ca(2+)](i)) mobilization (EC(50)=570+/-83 nM in h-TM; EC(50)=900+/-320 nM in h-CM). Cabergoline-induced [Ca(2+)](i) mobilization in h-TM and h-CM cells was potently antagonized by a 5HT(2A)-selective antagonist (M-100907, K(i)=0.29-0.53 nM). Cabergoline also stimulated [Ca(2+)](i) mobilization more potently via human cloned 5HT(2A) (EC(50)=63.4+/-10.3 nM) than via 5HT(2B) and 5HT(2C) receptors. In h-CM cells, cabergoline (1 microM) stimulated production of pro-matrix metalloproteinases-1 and -3 and synergized with forskolin to enhance cAMP production. Cabergoline (1 microM) perfused through anterior segments of porcine eyes caused a significant (27%) increase in outflow facility. Topically administered cabergoline (300-500 microg) in Dutch-belted rabbit eyes yielded 4.5 microMM and 1.97 microM levels in the aqueous humor 30 min and 90 min post-dose but failed to modulate intraocular pressure (IOP). However, cabergoline was an efficacious IOP-lowering agent in normotensive Brown Norway rats (25% IOP decrease with 6 microg at 4h post-dose) and in conscious ocular hypertensive cynomolgus monkeys (peak reduction of 30.6+/-3.6% with 50 microg at 3h post-dose; 30.4+/-4.5% with 500 microg at 7h post-dose). In ketamine-sedated monkeys, IOP was significantly lowered at 2.5h after the second topical ocular dose (300 microg) of cabergoline by 23% (p<0.02) and 35% (p<0.004) in normotensive and ocular hypertensive eyes, respectively. In normotensive eyes, cabergoline increased uveoscleral outflow (0.69+/-0.7 microL/min-1.61+/-0.97 microL/min, n=13; p<0.01). However, only seven of the eleven ocular hypertensive monkeys showed significantly increased uveoscleral outflow. These data indicate that cabergoline's most prominent agonist activity

Topics: Animals; Antihypertensive Agents; Aqueous Humor; Biological Availability; Cabergoline; Calcium; Cats; Cells, Cultured; CHO Cells; Cricetinae; Cricetulus; Disease Models, Animal; Drug Evaluation, Preclinical; Ergolines; Humans; Intraocular Pressure; Macaca fascicularis; Ocular Hypertension; Rabbits; Rats; Species Specificity

Implantation of a retrogradely-shed endometrium during menstruation requires an adequate blood supply. The endometrium has angiogenic potential, and endometriotic lesions grow in areas with a rich vascularization, suggesting that angiogenesis is a prerequisite for endometriosis development. Targeting vascular endothelial growth factor (VEGF) leads to an inhibition of endometriosis. Dopamine and its agonists, such as cabergoline (Cb2), promote VEGF receptor-2 (VEGFR-2) endocytosis in endothelial cells, preventing VEGF-VEGFR-2 binding and reducing neoangiogenesis. The aim of this study was to evaluate the anti-angiogenic properties of Cb2 on growth of established endometriosis lesions and investigate the molecular mechanisms by which Cb2 exerts the anti-angiogenic effect.. Human endometrium fragments were implanted in female nude mice peritoneum, and mice were treated with vehicle, 0.05 or 0.1 mg/kg/day oral Cb2 for 14 days. After treatment, the implants were processed to assess proliferative activity, neoangiogenesis, VEGFR-2 phosphorylation and angiogenic gene expression.. A significant decrease in the percentage of active endometriotic lesions (P < 0.05) and cellular proliferation index (P < 0.001) was found with Cb2 treatment. Neoangiogenesis was reduced by Cb2 treatment, as observed at gross morphological level and by significant changes in gene expression. The degree of VEGFR-2 phosphorylation was significantly lower in Cb2-treated animals than controls.. Cb2 treatment in experimental endometriosis has an anti-angiogenic effect acting through VEGFR-2 activation. These findings support the testing of dopamine agonists as a novel therapeutic approach to peritoneal endometriosis in humans.

Topics: Animals; Cabergoline; Cell Proliferation; Disease Models, Animal; Dopamine Agonists; Endometriosis; Ergolines; Female; Gene Expression Regulation; Humans; Mice; Neovascularization, Pathologic; Phosphorylation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

The dorsomedial medulla oblongata (DMM) includes the solitary tract nucleus and the hypoglossal nucleus, to which 5-HT neurons project. Effects of 5-HT in the DMM on ventilatory augmentation and airway dilation are mediated via 5-HT2 receptors, which interact with the CO(2) drive. The interaction may elicit cycles between hyperventilation with airway dilation and hypoventilation with airway narrowing. In the present study, effects of 5-HT2 receptors in the DMM on hypoxic ventilatory and airway responses were investigated, while 5-HT release in the DMM was monitored. Adult male mice were anesthetized, and then a microdialysis probe was inserted into the DMM. The mice were placed in a double-chamber plethysmograph. After recovery from anesthesia, the mice were exposed to hypoxic gas (7% O(2) in N(2)) for 5 min with or without a 5-HT2 receptor antagonist (LY-53857) perfused in the DMM. 5-HT release in the DMM was increased by hypoxia regardless of the presence of LY-53857. Immediate onset and the peak of initial hypoxic hyperventilatory responses were delayed. Subsequent ventilatory decline and airway dilation during initial hypoxic hyperventilation were suppressed with LY-53857. These results suggest that 5-HT release increased by hypoxia acts on 5-HT2 receptors in the DMM, which contributes to the immediate onset of initial hypoxic hyperventilation, airway dilation, and subsequent ventilatory decline. Hypoxic ventilatory and airway responses mediated via 5-HT2 receptors in the DMM may play roles in immediate rescue and defensive adaptation for hypoxia and may be included in periodic breathing and the pathogenesis of obstructive sleep apnea.

Topics: Airway Resistance; Animals; Body Weight; Disease Models, Animal; Ergolines; Hyperventilation; Hypoxia; Lung; Male; Medulla Oblongata; Mice; Mice, Inbred C57BL; Microdialysis; Plethysmography; Pulmonary Ventilation; Receptors, Serotonin, 5-HT2; Respiratory Mechanics; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Sleep Apnea, Obstructive; Time Factors

Emotional disturbances, depressive mood, anxiety, aggressive behavior, and memory impairment are the common psychiatric features associated with temporal lobe epilepsy (TLE). The present study was carried out to investigate the role of Bacopa monnieri extract in hippocampus of pilocarpine-induced temporal lobe epileptic rats through the 5-HT(2C) receptor in relation to depression. Our results showed upregulation of 5-HT(2C) receptors with a decreased affinity in hippocampus of pilocarpine-induced epileptic rats. Also, there was an increase in 5-HT(2C) gene expression and inositol triphosphate content in epileptic hippocampus. Carbamazepine and B. monnieri treatments reversed the alterations in 5-HT(2C) receptor binding, gene expression, and inositol triphosphate content in treated epileptic rats as compared to untreated epileptic rats. The forced swim test confirmed the depressive behavior pattern during epilepsy that was nearly completely reversed by B. monnieri treatment.

Topics: Animals; Anticonvulsants; Bacopa; Carbamazepine; Disease Models, Animal; Epilepsy; Ergolines; Hippocampus; Inositol 1,4,5-Trisphosphate; Male; Pilocarpine; Plant Preparations; Protein Binding; Radioligand Assay; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT2C; Serotonin Antagonists; Statistics, Nonparametric; Swimming; Tritium; Up-Regulation

Levodopa-induced dyskinesias are one of the major limiting side effects encountered in the treatment of Parkinson's disease. Dopamine agonists of the D2 family are less prone to induce these abnormal involuntary movements (AIMs), and in some instances it has been proposed that they could counteract them once already established. As differences in the plasma half-life of a given DA agonist could be related with a greater or lesser propensity to induce or to counteract AIMs, we compared the effects of two D2 agonists (cabergoline and pramipexole) with different half-lives, and levodopa, at doses producing similar improvement in purposeful forelimb use, in rats with severe nigrostriatal lesion, previously sensitized to levodopa. The same therapeutic regime was subsequently used in pharmacologically naïve rats. We found that: (i) prior induction of AIMs by levodopa administration primes rats for the occurrence of AIMs during mono-therapy with pramipexole (but not with cabergoline); (ii) an intervening period of D2 agonist mono-therapy does not modify the severity of AIMs induced by subsequent mono-therapy with levodopa; iii. de novo treatment with D2 agonists is associated with a lower risk of AIMs (regardless of the severity of the lesion) and does not modify AIMs during subsequent mono-therapy with levodopa. An unexpected finding was that prior levodopa therapy sensitized rats to the therapeutic effects of D2 agonists given in mono-therapy. In summary, the use of the rat with nigrostriatal lesion to model relevant therapeutic conditions does not support that D2 agonists prevent the development of AIMs during subsequent levodopa mono-therapy or can revert the dysfunction underlying it.

Topics: Amphetamine; Animals; Antiparkinson Agents; Behavior, Animal; Benzothiazoles; Cabergoline; Disease Models, Animal; Dopamine Antagonists; Drug Interactions; Dyskinesia, Drug-Induced; Ergolines; Female; Levodopa; Mesencephalon; Oxidopamine; Parkinsonian Disorders; Pramipexole; Rats; Rats, Wistar; Stereotyped Behavior; Tyrosine 3-Monooxygenase

Although it has been suggested that ergot derivatives may play a role in antiglaucoma therapy, little attention has been paid to the ocular hypotensive action of these drugs. Having previously reported that topical natural ergot alkaloids ergocristine alpha-ergocryptine and ergocornine dose-dependently reduce intraocular pressure in ocular normotensive and alpha-chymotrypsin-induced ocular hypertensive rabbits, the aim of the present work was to compare the effect of ergocristine, alpha-ergocryptine and ergocornine on the intraocular pressure and aqueous humor dynamics in ocular normotensive and alpha-chymotrypsin-induced ocular hypertensive rabbits, in order to further explore the ocular actions of these compounds.. Experiments were conducted in albino ocular normotensive and hypertensive rabbits by intracameral injection of alpha-chymotrypsin. Intraocular pressure responses to drug vehicle and seven different doses of topical natural ergot alkaloids were examined, in order to obtain dose-response relationships for comparing the intraocular pressure-lowering effect and potency of these drugs. Tonographies were also performed to ascertain the actions of natural ergot alkaloids on aqueous humor dynamics.. All natural ergot alkaloids tested reduced intraocular pressure in a dose-related fashion. The ocular hypotensive effect was greater in alpha-chymotrypsin-induced ocular hypertensive rabbits for the three compounds tested. All natural ergot alkaloids tested decreased both tonographic outflow facility and, to a greater extent, aqueous humor inflow in ocular normotensive and in alpha-chymotrypsin-induced ocular hypertensive rabbits.. Taken together, our data suggest that these compounds decrease both tonographic outflow facility and, to a greater extent, aqueous humor inflow, which explains their final effect in ocular normotensive and in alpha-chymotrypsin-induced ocular hypertensive rabbits. Reductions in aqueous humor inflow observed after topical application of natural ergot alkaloids in alpha-chymotrypsin-induced ocular hypertensive rabbits can only be explained by a marked inhibition of active secretion of aqueous humor, since processes involved in aqueous humor formation may probably be altered after alpha-chymotrypsin injection.

Topics: Administration, Topical; Animals; Aqueous Humor; Chymotrypsin; Disease Models, Animal; Dose-Response Relationship, Drug; Ergolines; Ergot Alkaloids; Intraocular Pressure; Ocular Hypertension; Rabbits; Tonometry, Ocular

No specific treatment is available for ovarian hyperstimulation syndrome (OHSS), the most important complication in infertile women treated with gonadotropins. OHSS is caused by increased vascular permeability (VP) through ovarian hypersecretion of vascular endothelial growth factor (VEGF)-activating VEGF receptor 2 (VEGFR-2). We previously demonstrated in an OHSS rodent model that increased VP was prevented by inactivating VEGFR-2 with a receptor antagonist (SU5416). However, due to its toxicity (thromboembolism) and disruption of VEGFR-2-dependent angiogenic processes critical for pregnancy, this kind of compound cannot be used clinically to prevent OHSS. Dopamine receptor 2 (Dp-r2) agonists, used in the treatment of human hyperprolactinemia including pregnancy, inhibit VEGFR-2-dependent VP and angiogenesis when administered at high doses in animal cancer models. To test whether VEGFR-2-dependent VP and angiogenesis could be segregated in a dose-dependent fashion with the Dp-r2 agonist cabergoline, a well-established OHSS rat model supplemented with prolactin was used. A 100 microg/kg low-dose Dp-r2 agonist cabergoline reversed VEGFR-2-dependent VP without affecting luteal angiogenesis through partial inhibition of ovarian VEGFR-2 phosphorylation levels. No luteolytic effects (serum progesterone levels and luteal apoptosis unaffected) were observed. Cabergoline administration also did not affect VEGF/VEGFR-2 ovarian mRNA levels. Results in the animal model and the safe clinical profile of Dp-r2 agonists encouraged us to administer cabergoline to oocyte donors at high risk for developing the syndrome. Prophylactic administration of cabergoline (5-10 microg/kg x d) decreased the occurrence of OHSS from 65% (controls) to 25% (treatment). Therefore, a specific, safe treatment for OHSS is now available.

Topics: Animals; Cabergoline; Capillary Permeability; Corpus Luteum; Disease Models, Animal; Dopamine Agonists; Ergolines; Female; Neovascularization, Physiologic; Ovarian Hyperstimulation Syndrome; Phosphorylation; Rats; Rats, Wistar; Receptors, Dopamine D2; RNA, Messenger; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Levodopa therapy is the gold standard for symptomatic treatment of Parkinson's disease (PD), but levodopa and/or dopamine (DA)-induced neurotoxicity have been reported in both in vitro and in vivo experimental studies. To clarify the beneficial effects of combining DA agonists with levodopa in PD, the present study examines the effects of cabergoline, a DA agonist, on the levodopa-induced abnormal increase of lipid peroxidation (LPO) and caspase activities in 6-hydroxydopamine (6-OHDA)-lesioned mice. Daily treatments of levodopa/carbidopa for 7 days beginning at 1 day after 6-OHDA i.c.v. injection increased striatal DA levels and glutathione (GSH) contents. Furthermore, a high dose of levodopa/carbidopa (50/12.5 mg/kg) enhanced LPO and caspase-3, -8, and -9 activities in 6-OHDA-lesioned mouse brain. However, when levodopa/carbidopa (50/12.5 mg/kg) was combined with cabergoline (0.25 mg/kg), the effect reduced levodopa's enhancement of caspase-3, -8, and -9 activities in the 6-OHDA-lesioned mouse brain. In addition, the GSH-increasing effect of the combined cabergoline and levodopa/carbidopa treatment was stronger than that of the levodopa/carbidopa mono-treatment. Moreover, cabergoline prevented levodopa-induced abnormal increases of LPO in 6-OHDA-lesioned mice. These results indicate that such prevention is attributable mainly to the increase in GSH content and to the inhibition of caspase activities in 6-OHDA-lesioned mice.

Topics: 3,4-Dihydroxyphenylacetic Acid; Analysis of Variance; Animals; Cabergoline; Carbidopa; Caspases; Disease Models, Animal; Dopamine; Dopamine Agents; Dopamine Agonists; Drug Combinations; Drug Interactions; Enzyme Activation; Ergolines; Glutathione; Homovanillic Acid; Levodopa; Male; Mice; Mice, Inbred ICR; Neurotoxicity Syndromes; Oxidopamine; Thiobarbituric Acid Reactive Substances

Dopamine receptor agonists are protective in different models of neurodegeneration by both receptor-dependent and -independent mechanisms. We used SH-SY5Y cells, differentiated into neuron-like type, to evaluate if cabergoline, a dopamine D2 receptor agonist endowed with anti-oxidant activity, protects the cells against ischemia (oxygen-glucose deprivation model). Cabergoline protected the cells from ischemia-induced cell death in a concentration-dependent manner (EC(50)=1.2 microM), as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, lactate dehydrogenase (LDH) release, and fluorescein diacetate-propidium iodide staining. This effect, observed even when the drug was added after oxygen-glucose deprivation, was not mediated by either dopamine D2 receptor activation or anti-apoptotic Bcl-2 protein over-expression (Western blotting analysis), but was linked to a reduction in cellular free radical loading (2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining) and membrane lipid peroxidation (thiobarbituric acid-reacting test). In conclusion, cabergoline protects in vitro neurons against ischemia-induced cell death, suggesting its possible use in the therapy of other neurodegenerative diseases in addition to Parkinson's disease.

Topics: Animals; Antioxidants; Cabergoline; Cell Death; Cell Hypoxia; Cell Line, Transformed; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Ergolines; Free Radical Scavengers; Free Radicals; Gene Expression; Genes, bcl-2; Glucose; Haloperidol; Humans; Ischemia; Neurons; Thiobarbituric Acid Reactive Substances; Time Factors; Tretinoin; Vitamin E

Levodopa continues to be the most effective agent for the symptomatic treatment of Parkinson's disease (PD). But over time, initial benefits decline in efficacy because of a rise in adverse effects such as dyskinesias. The pathophysiology of levodopa-induced dyskinesias (LID) is not completely understood, but it appears to result from deficient regulation by dopamine of corticostriatal glutamatergic inputs leading to a cascade of neurochemical changes in the striatum and the output pathways. In the present study, we examined if the addition of small doses of cabergoline (a long-acting D(2) receptor agonist) to levodopa could prevent LID. The major hypothesis is that sustained activation of postsynaptic D(2) receptors on medium spiny neurons even by small doses of cabergoline could prevent or reduce LID. The minor hypothesis, and the more controversial of the two, is that the long-acting stimulation by small doses of cabergoline could diminish the release of glutamate by the corticostriatal pathway and prevent LID. Eight MPTP-treated monkeys with a long-standing and stable parkinsonian syndrome and having never received dopaminergic agents were used. Two groups of four were treated for 1 month with levodopa/benserazide administered orally (100 mg/25 mg). The second group received in addition a threshold dose of cabergoline (dose ranging from 0.015 to 0.035 mg/kg, SC). During the treatment, we observed LID in the levodopa group but not in the group receiving levodopa+cabergoline. Furthermore, the combination produced a comparable antiparkinsonian effect in terms of quality but prolonged the duration (by 1 to 2 hours) and increased the locomotion (mean for 2 weeks congruent with 104%). Our data suggest that a small dose of a long-acting D(2) agonist combined with high doses of levodopa could be preventive of LID in patients with PD and could be an alternative to using antiglutamatergic agents for this purpose.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Behavior, Animal; Cabergoline; Disease Models, Animal; Dopamine Agonists; Drug Administration Schedule; Dyskinesia, Drug-Induced; Ergolines; Female; Locomotion; Macaca fascicularis; Parkinson Disease; Posture

The effects of short and long-acting dopamine agonists on sensitized dopaminergic transmission in an animal model of Parkinson's disease were investigated. Rats with 6-hydroxydopamine (6-OHDA) lesions of the left nigrostriatal dopaminergic pathway were pre-exposed i.p. to 50 mg/kg methyl levodopa for 10 days. After a 7-day withdrawal period, these animals were treated with saline i.p., 0.05 mg/kg apomorphine s.c., or 0.5 mg/kg cabergoline i.p., once daily for 7 days. On the 8th day, rats in each treatment group received a challenge dose of 0.05 mg/kg apomorphine or saline s.c. The temporal changes in the number of rotations away from the 6-OHDA lesion side were evaluated after the challenge. The apomorphine challenge increased the number of rotations more markedly in the apomorphine pretreated rats than in the other pretreatment groups. In cabergoline pretreated rats, the number of rotations was significantly lower than that of saline-pretreated animals. Pretreatment with saline did not alter the apomorphine sensitivity of rotational behavior. These findings suggest that the repeated administration of long-acting dopamine agonists may reduce sensitized dopaminergic transmission in dopamine-depleted rats, whereas short-acting ones may further enhance sensitization of the transmission process.

Topics: Adrenergic Agents; Animals; Antiparkinson Agents; Apomorphine; Behavior, Animal; Cabergoline; Corpus Striatum; Disease Models, Animal; Dopamine Agonists; Drug Antagonism; Ergolines; Levodopa; Male; Oxidopamine; Rats; Rats, Sprague-Dawley; Stereotyped Behavior; Synaptic Transmission

Topics: Aminoquinolines; Animals; Behavior, Animal; Benzazepines; Cabergoline; Disease Models, Animal; Dopamine Agonists; Ergolines; Female; Gene Expression; Imidazoles; Infusion Pumps, Implantable; Macaca fascicularis; Motor Activity; Parkinsonian Disorders; Pulse Therapy, Drug; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Dopamine D3; RNA, Messenger

1. Chronic treatment for one month with the long-acting dopamine D2-like agonist cabergoline (0.25 mg/kg s.c. every 48 hours), had despite partial tolerance, sustained antiparkinsonian activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Parkinsonian monkeys (Macaca fascicularis). 2. Cabergoline treatment decreased by half striatal D2 receptor binding density measured by [3H]spiperone autoradiography versus untreated MPTP monkeys. No change in D2 mRNA measured by in situ hybridization and D2 receptor immunostaining was observed. 3. No change in either D1 receptor binding density or D1 receptor mRNA levels was observed in cabergoline-treated MPTP-monkeys compared to untreated MPTP-monkeys, suggesting receptor subfamily specificity of cabergoline. 4. The present results suggest that the cabergoline-induced behavioral partial tolerance is accompanied by a decrease in D2 receptor binding but not due to alterations in the steady state of D2 mRNA levels.

Topics: Animals; Antiparkinson Agents; Binding Sites; Cabergoline; Disease Models, Animal; Ergolines; Female; In Situ Hybridization; Macaca fascicularis; Parkinson Disease; Receptors, Dopamine D1; Receptors, Dopamine D2

To study specific serotonin (5-hydroxytryptamine [5-HT]) receptor subtype antagonists in an animal model of posthypoxic myoclonus.. Although serotonergic system dysfunction is implicated in posthypoxic myoclonus, anatomic specificity and linkage to receptor subtypes are not delineated.. The authors performed a pharmacologic study to identify specific serotonin receptor subtype antagonists effective in inhibiting myoclonus in posthypoxic rats. Sprague-Dawley rats underwent cardiac arrest for 8 minutes and were resuscitated. On the day of pharmacologic testing, animals were rated every 10 minutes at -30 minutes to time 0 (drug injection) and from +60 to +150 minutes. Using a blinded methodology, animals were injected with normal saline, vehicle, or one of seven serotonin antagonists given at a dose that maintains serotonin receptor subtype specificity: WAY100135 (5-HT1A), methiothepin mesylate (5-HT1B/1D/2), mesulergine hydrochloride (5-HT2A/2B), GR 127935 (5-HT1D), SR 46349 (5-HT2), ondansetron (5-HT3), or GR 125487 (5-HT4). Drugs that produced a significant decrease in myoclonus compared with the control were studied in a dose-response study with six doses across a range from the original dose studied to 10% of that dose.. Two drugs were significantly different from placebo: methiothepin mesylate and mesulergine hydrochloride. GR 127935 showed a trend toward reducing myoclonus. Dose-response studies showed that all doses of methiothepin mesylate and the three highest doses of mesulergine hydrochloride inhibited myoclonus effectively.. 5-HT1B, 5-HT2A/2B, and possibly 5-HT1D receptor subtypes likely play a role in posthypoxic myoclonus. More specific 5-HT antagonists that affect these receptor subtypes are candidates for future testing in this model and in Lance-Adams syndrome.

Topics: Acoustic Stimulation; Animals; Brain Chemistry; Disease Models, Animal; Dose-Response Relationship, Drug; Ergolines; Heart Arrest; Hypoxia; Hypoxia, Brain; Male; Methiothepin; Myoclonus; Oxadiazoles; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin Antagonists

We aimed to develop an anovulation model, using sulpiride-induced hyperprolactinemia in common marmosets. The serum prolactin level gradually increased during the twice-daily administration of sulpiride and reached a plateau after 4 days. Sulpiride produced as big a response at 10 mg kg(-1) as at 50 mg kg(-1). In this study, the length of the ovarian cycle was approximately 30 days in normal common marmosets. Serum progesterone and estradiol levels showed no consistent change during the first 2 months of treatment with sulpiride. When treatment with sulpiride had been continued for more than 2 months, serum progesterone and estradiol levels fell to within the range seen in the follicular phase of the normal cycle and absence of ovulation was recognized by laparoscopy. A single oral administration of cabergoline (at doses between 0.01 and 0.1 mg kg(-1)) dose dependently reduced the elevated serum prolactin level. Bromocriptine (at an oral dose of 10 mg kg(-1)) also reduced the serum prolactin level at 4 and 8 h after its administration. With bromocriptine, the prolactin level had recovered at 24 h, but with cabergoline at doses of 0.05 mg kg(-1) or more, it had still not recovered at 48 h. In anovulatory common marmosets, oral administration of cabergoline at a daily dose of 0.05 mg kg(-1) restored ovarian function and resulted in ovulation in 100% of the group (following a reduction in the serum prolactin level). Bromocriptine at a daily oral dose of 10 mg kg(-1) resulted in ovulation in 67% of the group, but this dose was about 200 times higher than the dose of cabergoline. We could produce an anovulatory model induced by sulpiride repeatedly administered over a long time period. It is suggested that, in this anovulatory model in common marmosets, cabergoline has a potent and long-lasting action as a dopamine D2 receptor agonist, and thus could be a useful drug for the treatment of galactorrhea and hyperprolactinemic amenorrhea and/or anovulation.

Topics: Animals; Anovulation; Bromocriptine; Cabergoline; Callithrix; Disease Models, Animal; Dopamine Agonists; Dopamine Antagonists; Ergolines; Estradiol; Female; Hyperprolactinemia; Menstrual Cycle; Progesterone; Prolactin; Sulpiride; Time Factors

Methods for the assessment of akinesia in the unilateral rat Parkinson model have so far been lacking. The experiments reported here evaluate the usefulness of a new "stepping test" to monitor forelimb akinesia in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the mesencephalic dopamine (DA) system, and to assess the ability of DA-receptor agonists and fetal DA neuron transplants to reverse these deficits. The 6-OHDA lesion induced marked and long-lasting impairments in the initiation of stepping movements with the contralateral paw. Systemic injections of low doses (chosen to be subthreshold for induction of rotation) of the mixed D1 and D2 receptor agonist apomorphine, the D1-selective agonist SKF 38393, and to a lesser extent also the D2-selective agonist quinpirole were effective in reversing these deficits. Similar effects was seen after a subrotational dose of L-dopa, whereas amphetamine had no effect. Fetal nigral transplants, implanted as multiple deposits in the ipsilateral caudate-putamen and substantia nigra, restored initiation of stepping to a similar degree as the DA agonists. Nigral grafts placed in substantia nigra alone were also effective, although the improvement was less pronounced. Apomorphine, at a dose effective in the lesion-only animals, had no additive effect in the grafted rats, whereas amphetamine appeared to further improve stepping in the rats with intranigral transplants. Identical experiments were performed on skilled forelimb use in the so-called staircase test. Interestingly, neither the DA agonist drugs nor the nigral transplants had any effects on the lesion induced deficits in this more complex task. The results show that forelimb stepping is a highly useful test to monitor lesion-/and transplant-induced changes in forelimb akinesia, a behavioral parameter that may be analogous to limb akinesia and gait problems seen in patients with Parkinson's disease.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Analysis of Variance; Animals; Apomorphine; Brain Tissue Transplantation; Carbidopa; Dextroamphetamine; Disease Models, Animal; Dopamine; Dopamine Agonists; Ergolines; Female; Fetal Tissue Transplantation; Forelimb; Functional Laterality; Levodopa; Motor Activity; Movement Disorders; Norepinephrine; Oxidopamine; Parkinson Disease; Quinpirole; Rats; Rats, Sprague-Dawley; Rotation; Substantia Nigra; Transplantation, Heterotopic

Acetylcholine (ACh) release was measured by microdialysis. Addition of 10 nM L-DOPA to the perfusate significantly decreased ACh release, from the striatum of rats lesioned with 6-hydroxydopamine (6-OHDA), but not sham-operated rats. The L-DOPA-induced decrease was not affected by (-)-sulpiride which completely blocked D2- and D3-agonist-induced decrease in ACh release in lesioned rats. Neither 10 nM D-DOPA nor 100 nM dopamine caused by any change in ACh release. These findings suggest that L-DOPA-sensitive mechanisms are supersensitized in Parkinson's disease model rats.

Topics: Acetylcholine; Analysis of Variance; Animals; Corpus Striatum; Disease Models, Animal; Dopamine Agonists; Drug Synergism; Ergolines; Levodopa; Male; Oxidopamine; Parkinson Disease, Secondary; Quinpirole; Rats; Rats, Sprague-Dawley; Tetrahydronaphthalenes

The model of sleep deprivation in rats by the platform method has been extensively studied in our laboratory as a possible animal model of mania. At the end of the period of sleep deprivation, the rat does not fall asleep as soon as it is returned to its home cage, but shows a period of wakefulness of about 30 min, during which the animal presents a cohort of symptoms that appear to mimic those present in idiopathic mania. In particular, during this period the animal displays insomnia, a high degree of hyperactivity, irritability, aggressiveness, hypersexuality and stereotypy. Haloperidol (0.2 mg/kg) was effective in reducing latency to sleep, while L-sulpiride was much weaker (< 50 mg/kg). The dopamine D1 receptor antagonist SCH 23390 exhibited an extremely high potency and efficacy in reducing sleep latency, a significant effect being observed with 3 micrograms/kg. The administration of the specific D1 receptor agonist SKF 38393 markedly prolonged the period of insomnia with the correlated behavioral syndrome. When lithium was added to the diet and consumed during the sleep deprivation period in adequate amounts to produce serum lithium levels of 0.7-1.0 mEq/l, sleep latency and locomotor activity were significantly reduced. The administration of naloxone (1-10 mg/kg) reduced the latency to sleep in a dose-related manner. By contrast, morphine (1 and 5 mg/kg, i.p.), beta-endorphin and [D-Ala2,D-Leu5]enkephalin (i.c.v., 2 and 1 micrograms, respectively) markedly prolonged the insomnia. The model not only represents a confirmation in the rat that sleep loss often precedes and may trigger a manic episode in man, but suggests that an opioid-dopamine interaction may play a pathogenetic role in mania.

Topics: Animals; Bipolar Disorder; Disease Models, Animal; Dopamine; Dopamine Agonists; Dose-Response Relationship, Drug; Ergolines; Lithium; Narcotics; Quinpirole; Rats; Sleep Deprivation

Serotonin (5-HT) may play a role in exacerbating thrombosis and coronary spasm during myocardial ischemia, but its role in mediating myocardial damage directly is not clear. We determined the effect of the 5-HT2 receptor antagonists cinanserin (0.1-10 microM), ketanserin (0.3-10 microM), and LY 53857 (1-10 microM) on time to contracture, recovery of contractile function, and lactate dehydrogenase (LDH) release after 25-min global ischemia and 30-min reperfusion in isolated rat heart. All 5-HT2 antagonists significantly increased time to contracture in a concentration-dependent manner (EC25 = 1.6, 5.5, and 6.1 microM for cinanserin, ketanserin, and LY 53857, respectively). These compounds also significantly reduced LDH release and improved recovery of contractile function during reperfusion. 5-HT > or = 30 microM significantly reduced time to contracture, indicating a proischemic effect. The proischemic effect of 5-HT was abolished by ketanserin and cinanserin. Inhibition of 5-HT synthesis by parachlorophenylalanine resulted in significant cardioprotection, further indicating the involvement of 5-HT in the pathogenesis of ischemia in this model. Although cinanserin and ketanserin had alpha 1-adrenoceptor blocking effects, LY 53857 was devoid of this activity at concentrations exhibiting cardioprotection. Therefore, 5-HT may exacerbate ischemic injury in rat heart, and this exacerbation appears to be mediated specifically by 5-HT2 receptors.

Topics: Animals; Cinanserin; Disease Models, Animal; Ergolines; Heart; Hemodynamics; Ketanserin; L-Lactate Dehydrogenase; Male; Muscle, Smooth, Vascular; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha; Serotonin Antagonists

The anti-immobility effect of fluoxetine (40 mg kg-1) in the forced swimming test in mice was antagonized by the 5-HT1c/2 antagonist mesulergine (7.5 mg kg-1) and the dopamine D2 antagonist (+/-)-sulpiride (12.5 mg kg-1) but not by the 5-HT2/1C antagonist ritanserine (2 mg kg-1), the 5-HT1A/1B antagonist (-)-propranolol (20 mg kg-1) or the 5-HT3 antagonist DAU 6215 (0.1 mg kg-1). All compounds were administered intraperitoneally (i.p.) 6 min before fluoxetine, given i.p. 30 min before testing. The anti-immobility effect of fluoxetine was also prevented by pretreatment with p-chlorophenylalanine (300 mg kg-1 twice daily for 3 days) which produced an 80% reduction of 5-HT in brain. The results suggest that fluoxetine reduces immobility time in mice forced to swim, by acting indirectly through a mesulergine-sensitive site, probably the 5-HT1C receptor.

Topics: Animals; Behavior, Animal; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Ergolines; Fluoxetine; Immobilization; Male; Mice; Neurotransmitter Uptake Inhibitors; Receptors, Serotonin; Swimming

The alleged selective, high efficacy dopamine D1 receptor agonist, SKF 81297 (0.05-0.3 mg/kg i.m.), induced rotational behaviour away from the lesion and stimulated use of the dominant right hand in unilaterally (left side) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned rhesus monkeys (Macaca mulatta). The effects of SKF 81297 were completely blocked by the dopamine D1 receptor antagonist, SCH 23390 (0.05 mg/kg), but not by the dopamine D2 receptor antagonist, remoxipride (1 mg/kg), and were similar to those induced by the selective dopamine D2 agonist, LY 171555 (0.01 mg/kg). These results suggest a functional stimulatory role for the dopamine D1 receptor on motor behaviour in a non-human primate model of Parkinson's disease when stimulated with a high efficacy selective dopamine D1 receptor agonist.

Topics: Analysis of Variance; Animals; Benzazepines; Disease Models, Animal; Dopamine Agents; Ergolines; Macaca mulatta; Male; Motor Activity; MPTP Poisoning; Parkinson Disease; Quinpirole; Remoxipride

Rats with limbic system damage display increases in responsivity to sensory stimulation and changes in the sensitivity to amphetamine, suggesting that their condition may parallel that of human schizophrenia. This experiment examined locomotion and stereotyped behavior in mature, male rats that had received aspirative lesions of the hippocampus, control lesions of the overlying parietal cortex, or were unoperated controls. Locomotion, measured as photocell beam breaks, was recorded during 2- or 3-h test sessions. Behavioral stereotypy was simultaneously rated. Hippocampal lesioned rats exhibited a selective enhancement in locomotion following D-amphetamine (0.0-5.6 mg/kg) when compared to animals in the control groups. Similar results were observed following injections of apomorphine (0.0-0.25 mg/kg), a mixed D1 and D2 agonist. In order to determine if D1 or D2 receptors were involved in this increased locomotion, the D1 agonist SKF 38393 (0.0-15 mg/kg) and the D2 agonist quinpirole (0.0-0.5 mg/kg) were tested alone and in combination. Hippocampal-ablated rats showed significantly increased locomotion only in response to quinpirole, suggesting that these lesion-induced increases were largely mediated by D2 receptors. When both drugs were administered together, SKF 38393 further enhanced the locomotor stimulating effects of quinpirole in hippocampal lesioned rats, indicating a synergistic interaction between D1 and D2 receptors in the modulation of locomotion. These findings provide further evidence of hippocampal modulation of locomotion and suggest that dopaminergic mechanisms in the nucleus accumbens, probably involving changes in receptor sensitivity, are involved. The results are discussed in relation to the functional roles of the nucleus accumbens and in terms of their implications for mental diseases including schizophrenia.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Apomorphine; Arousal; Brain Mapping; Dextroamphetamine; Disease Models, Animal; Dopamine Agents; Dose-Response Relationship, Drug; Ergolines; Hippocampus; Male; Motor Activity; Quinpirole; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2; Schizophrenia; Schizophrenic Psychology; Stereotyped Behavior

Eight Cebus apella monkeys were treated with haloperidol for 2 years. Five monkeys had developed mild oral tardive dyskinesia and all were primed for neuroleptic induced dystonia, thus serving as a model for both chronic and acute extrapyramidal side effects. In this model, the partial dopamine D2 receptor agonists SDZ HDC-912, SDZ HAC-911, terguride, (-)-3-(3-hydroxyphenyl)-N-propylpiperidine) ((-)-3-PPP) and SND 919 were tested for extrapyramidal side-effect liability. Their antipsychotic potential was also tested, using a dose of dextroamphetamine producing mild stereotypy and moderate motoric unrest. For comparison, the dopamine D2 receptor agonist, LY 171555 and antagonist, raclopride were used. In contrast to the other drugs tested, SDZ HAC-911 consistently reduced oral activity, P < 0.05 (at doses from 0.005 to 0.025 mg/kg). The relative dystonic potencies were raclopride > SDZ HDC-912 > SDZ HAC-911 = terguride. Neither (-)-3-PPP nor SND 919 produced dystonia, but had observable dopamine D2 receptor agonistic effects, (-)-3-PPP producing emesis at 1-4 mg/kg and SND 919 producing motoric unrest and stereotypy at 0.05-0.25 mg/kg. Comparing the antiamphetamine effects of the more antagonist-like drugs with raclopride, the relative potencies were terguride = SDZ HAC-911 > SDZ HDC-912 > raclopride. Comparing the antiamphetamine effects of the more agonist-like drugs with LY 171555, the relative potencies were SND 919 > (-)-3-PPP > LY 171555 in relation to motoric unrest, while neither (-)-3-PPP nor LY 171555 produced inhibition of stereotypy.

Topics: Administration, Oral; Amphetamine; Animals; Antipsychotic Agents; Behavior, Animal; Benzothiazoles; Cebus; Disease Models, Animal; Dopamine Agents; Dopamine D2 Receptor Antagonists; Dyskinesia, Drug-Induced; Dystonia; Ergolines; Female; Haloperidol; Lisuride; Male; Piperidines; Pramipexole; Quinpirole; Raclopride; Salicylamides; Thiazoles

Chronic exposure to mild unpredictable stress (CMS) has previously been found to cause an antidepressant-reversible decrease in the consumption of palatable sweet solutions. There is evidence that the effect of antidepressants in this model is mediated by an increase in transmission at dopamine (DA) synpases. The present study investigated whether another treatment known to increase the functional responsiveness of DA systems, intermittent administration of DA agonists, would have antidepressant-like effects. In three experiments in rats, CMS-induced decreases in sucrose consumption were reversed by three to four twice-weekly injections of quinpirole (100-200 micrograms/kg) or bromocriptine (2.5 mg/kg). The effects lasted for several weeks, and when they waned, could be reinstated by a single additional injection of quinpirole. As with tricyclic antidepressants, the effect of quinpirole was reversed by raclopride, administered acutely immediately prior to a sucrose consumption test; there were no changes in sucrose intake in nonstressed control animals. The results suggest that intermittent administration of DA agonists merits investigation as a novel strategy for the treatment of depression.

Topics: Animals; Arousal; Brain; Bromocriptine; Depressive Disorder; Disease Models, Animal; Dopamine Agents; Dose-Response Relationship, Drug; Drinking; Ergolines; Helplessness, Learned; Male; Motivation; Quinpirole; Rats; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D3; Taste

Studies from this laboratory have demonstrated that administration of the selective 5-HT2/1C antagonist LY53857 can block 5-HTP-induced response suppression. To further investigate the serotonergic mechanisms involved in this effect, we decided to test the capacity of LY53857 to block response suppression induced with two selective 5-HT agonists. After a 15 minute baseline period, rats trained to press a lever for milk reinforcement on a VI 1' schedule were given IP injections of 1.0 mg/kg DOI, or 1.0 mg/kg 8-OH-DPAT to induce response suppression. Subsequently, rats were injected with 1.0 mg/kg LY53857 1 hour prior to DOI- or 8-OH-DPAT-induced response suppression. Preinjections with LY53857 resulted in a 100% blockade of DOI-induced response suppression whereas the same dose did not block response suppression induced with 8-OH-DPAT. These results indicate that the 5-HTP-induced response suppression shows some pharmacological similarity to DOI-induced response suppression and may be mediated through 5-HT2 and/or 5-HT1C receptors.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Amphetamines; Animals; Behavior, Animal; Depression; Disease Models, Animal; Ergolines; Kinetics; Male; Rats; Rats, Inbred Strains; Reinforcement, Psychology; Serotonin Antagonists; Tetrahydronaphthalenes

The potential protective effects of serotonin receptor antagonism during the process of acute myocardial infarction were studied in anesthetized male dogs, which were subjected to a 90-min left circumflex coronary artery occlusion followed by 5 h of reperfusion. Either vehicle (0.9% NaCl) or the serotonin (5HT2) receptor antagonist LY53857 was infused i.v. at a dose of 0.5 mg/kg, followed by a constant infusion of 2 mg/kg/min beginning 5 min before left circumflex coronary artery occlusion and continuing throughout the duration of the ischemia and subsequent reperfusion. Verification of functional 5HT2 receptor antagonism in the circulating blood of the LY53857-treated dogs was monitored throughout the experiments by periodic assessment of ex vivo platelet reactivity to exogenous serotonin. After 5 h of reperfusion, the hearts were excised and analyzed utilizing histochemical staining with triphenyltetrazolium, which demarcates myocardial infarct size and anatomical area of myocardium at risk of infarction. There was not a significant reduction of infarct size with LY53857 treatment: control infarct/area at risk = 38.6 +/- 4.7%, n = 9 LY53857 infarct/area at risk = 33.4 +/- 3.8%, n = 6. Similarly, when myocardial infarct size was analyzed as a function of myocardial collateral blood flow, there were no significant effects of drug treatment on the relationship between collateral blood flow and infarct size. The effects of 5HT on neutrophil activation were determined by measuring the potential ability of 5HT to enhance the chemotactic peptide-induced production of superoxide. 5HT did not activate human neutrophils in vitro and LY53857 had no effect on neutrophil superoxide production.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Coronary Circulation; Disease Models, Animal; Dogs; Ergolines; Heart Rate; Leukocyte Count; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Neutrophils; Peroxidase; Platelet Count; Serotonin; Serotonin Antagonists; Superoxides; Ventricular Fibrillation

The present study was designed to evaluate the effectiveness of the ergoline 5HT2 receptor antagonist, LY53857 in a rabbit model of vascular arterial occlusion. LY53857 (1 and 10 microM) inhibited serotonin amplified platelet aggregation responses to threshold concentrations of ADP in rabbit platelets in vitro. LY53857 (1 microM) not only inhibited the serotonin component of rabbit platelet aggregation, but also inhibited in vitro aggregation induced by ADP (48.7 +/- 16.7% inhibition), collagen (76.1 +/- 15.9% inhibition) and U46619 (65.2 +/- 12.3% inhibition). The effectiveness of this ergoline 5HT2 receptor antagonist in blocking aggregation to ADP, collagen and U46619 may be related to its ability to inhibit a serotonin component of platelet aggregation since rabbit platelets possess high concentrations of serotonin that may be released during aggregation produced by other agents. Based on the effectiveness of LY53857 to inhibit rabbit platelet aggregation, we explored the ability of LY53857 to extend the time to carotid artery occlusion in rabbits following electrical stimulation of the artery. Reproducible carotid artery occlusion was induced in rabbits by moderate stenosis coupled to arterial cross clamping, followed by electrical stimulation. With this procedure, occlusion occurred at 47.0 +/- 7 min (n = 30) after initiation of the electrical stimulation. Animals pretreated with LY53857 (50 to 500 micrograms/kg i.v.) showed a delay in the time to carotid artery occlusion (at 100 micrograms/kg i.v. occlusion time extended to 164 +/- 16 min). Furthermore, ex vivo platelet aggregation from animals treated with LY53857 (300 micrograms/kg i.v.) resulted in 40.5% inhibition of platelet aggregation in response to the combination of ADP (1 microM) and serotonin (1 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arterial Occlusive Diseases; Carotid Artery Diseases; Disease Models, Animal; Ergolines; In Vitro Techniques; Male; Platelet Aggregation Inhibitors; Rabbits; Serotonin Antagonists; Time Factors

Prepulse inhibition of acoustic startle is deficient in schizophrenic patients and in animals injected with either direct or indirect dopamine (DA) agonists. The present experiments confirmed the hypothesis that the dopaminergic blockade of prepulse inhibition is attributable to the activation of D2 DA receptors. After systemic administrations of the D1 agonist SK&F 38393, the D2 agonist quinpirole, or a combination of the two, rats were tested for prepulse inhibition of the startle response by presenting acoustic stimuli or acoustic stimuli preceded by weak prepulses that inhibit startle. Although the D1 agonist SK&F 38393 had no effect on prepulse inhibition [0.3 to 30.0 mg/kg (1.03 to 102.82 mumols/kg)], the D agonist, quinpirole, blocked prepulse inhibition at doses of 0.3 mg/kg (1.17 mumols/kg) and 0.9 mg/kg (3.51 mumols/kg). Lower doses of quinpirole, 0.03 mg/kg (0.12 mumols/kg) and 0.1 mg/kg (0.39 mumols/kg), were ineffective. When an ineffective dose of quinpirole (0.1 mg/kg) was coadministered with 10.0 mg/kg SKF 38393, prepulse inhibition was reduced relative to saline controls. This reduction of prepulse inhibition is consistent with the synergistic effect of D1 and D2 DA receptor stimulation noted in studies of dopaminergic influences on stereotyped behavior in rats. These findings confirm that a disruption of sensorimotor gating results from D2 dopaminergic stimulation in the rat and extend the applicability of this animal model for the similar behavioral deficits exhibited by schizophrenic patients.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Acoustic Stimulation; Animals; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Ergolines; Humans; Male; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D2; Reflex, Startle; Schizophrenia; Schizophrenic Psychology

The regional distribution of high affinity [3H]5-HT recognition sites in the brain of several vertebrates (pigeon, rat, mouse, guinea-pig, cat, dog, monkey and human) was analyzed using in vitro autoradiography. The presence of subtypes of 5-HT1 binding sites was investigated by selective displacements with 8-OH-DPAT, mesulergine and (+/-)SDZ 21-009 at appropriate concentrations to block 5-HT1A, 5-HT1C and 5-HT1B sites respectively. In addition, 5-HT1A and 5-HT1C sites were directly visualized with the more selective radioligands [3H]8-OH-DPAT and [3H]mesulergine, respectively. In the pigeon brain, total [3H]5-HT binding sites were enriched in all telencephalic areas. Densely labelled regions were also present in the optic tectum and the brainstem. No binding was observed in the cerebellum. 8-OH-DPAT and mesulergine only displaced a small proportion of [3H]5-HT binding in most of the areas where high concentrations of 5-HT1 sites were found. (+/-)SDZ 21-009 did not affect [3H]5-HT binding in the regions examined. Taking into account our pharmacological studies, these results suggest that the majority of 5-HT1 sites belong to the 5-HT1D subtype in the pigeon brain. In the mammalian species investigated high levels of [3H]5-HT binding were found in the neo-cortex, hippocampal formation, basal ganglia and related structures (substantia nigra), raphe dorsalis, nucleus superior colliculus and choroid plexus. However, these brain areas were differentially enriched in subtypes of 5-HT1 recognition sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Aged; Animals; Autoradiography; Brain; Cats; Disease Models, Animal; Dogs; Ergolines; Female; Guinea Pigs; Humans; Macaca mulatta; Male; Mice; Movement Disorders; Receptors, Serotonin; Serotonin; Tetrahydronaphthalenes; Tritium

Topics: Animals; Anti-Anxiety Agents; Anxiety; Disease Models, Animal; Ergolines; Hypertension; Nicergoline; Norepinephrine; Rats; Rats, Inbred Strains; Scopolamine

The effect of nicergoline on cerebral blood flow (CBF), cerebrovascular resistance, the constriction of cerebral vessels caused reflectorily or by 5-hydroxytryptamine (5-HT) and on the transport of 5-HT in rat brain synaptosomes was studied using different experimental models. Nicergoline reduced cerebrovascular resistance in the carotid and vertebrobasilar system. The drug decreased carotid blood flow and local cortical CBF, preceded in some experiments by short-lasting CBF increase. Nicergoline almost completely inhibited brain vessels responses in the carotid and vertebrobasilar systems after tibial nerve stimulation. Simultaneously, inhibition of reflectory discharges of the sympathetic nerves was observed. Nicergoline showed an antiserotonin action by antagonizing the 5-HT effect on the cerebral circulation and inhibiting 5-HT-induced constriction of isolated rabbit basilar artery. The inhibition of uptake and enhancement of the release of 5-HT from brain synaptosomes indicates its ability to affect neuronal transmission in serotoninergic neurons. The effects of nicergoline are probably involved in the realization of its antimigraine action.

Topics: Animals; Basilar Artery; Cats; Cerebrovascular Circulation; Disease Models, Animal; Ergolines; In Vitro Techniques; Male; Migraine Disorders; Muscle Contraction; Muscle, Smooth, Vascular; Nicergoline; Rabbits; Rats; Serotonin; Synaptosomes; Vascular Resistance

Effects of lisuride, a central dopamine and serotonin agonist of the ergot type, in animal models of depression were investigated in comparison with those of desipramine, mianserin and rolipram. Lisuride, like desipramine and mianserin, inhibited reserpine-induced hypothermia in mice (0.5-5.0 mg/kg, i.p.) and suppressed muricide in olfactory bulbectomized rats (ED50 = 0.16 mg/kg, i.p.) in a dose-dependent manner. The anti-muricidal effect was slightly enhanced by the repeated administration of 0.25 mg/kg lisuride. Lisuride (0.05-0.25 mg/kg, i.p.), like desipramine, dose-dependently reduced the duration of immobility in rats forced to swim, and this effect was antagonized by haloperidol. The reduction of immobility time was enhanced by the repeated administration of lisuride; at the same time, the ambulation in rats increased. Furthermore, the immobility-reducing effects of desipramine and rolipram were markedly enhanced by the co-administration of a low dose of lisuride (0.025 mg/kg, i.p.), which by itself had no effect on the immobility time. These results indicate that lisuride may be useful for the treatment of depression and indicate that a low dose of lisuride may enhance the clinical effectiveness of antidepressants such as desipramine.

Topics: Agonistic Behavior; Animals; Body Temperature; Depression; Desipramine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Ergolines; Lisuride; Mice; Rats; Rats, Inbred Strains

Oral movements in rats, repetitive jaw movements (RJM), can be induced in a dose dependent manner by a specific D1 agonist, SKF 38393, and decreased by D2 receptor stimulation with a specific D2 agonist, LY 141865. Irreversible D1 receptor inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline severely reduced oral responses induced by SKF 38393, whereas such blockade of D2 receptors greatly augmented the D1 mediated behavior. Further, we found that chronic prolonged D2 receptor blockade following administration of fluphenazine decanoate facilitated repetitive jaw movements.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Benzazepines; Disease Models, Animal; Dopamine Antagonists; Dyskinesia, Drug-Induced; Ergolines; Fluphenazine; Male; Quinolines; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D2; Spiperone; Stereotyped Behavior

The partial dopamine agonist terguride (transdihydrolisuride) administered to four 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned hemiparkinsonian monkeys (at a dose of 4 mg/kg orally) induced marked contralateral turning that lasted 3.5 h. The 6-n-propyl derivative of terguride (proterguride) given to two monkeys (at a dose of 0.4 mg/kg orally) caused contralateral turning which lasted for more than 24 h but produced side effects such as dyskinesia and stereotype. After terguride treatment, cerebrospinal fluid concentrations of 3-methoxy-4-hydroxy-phenylglycol (MHPG) were increased, whereas concentrations of the metabolites dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were not significantly altered.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Disease Models, Animal; Ergolines; Female; Lisuride; Macaca fascicularis; Parkinson Disease, Secondary; Pyridines; Receptors, Dopamine

Terguride, an analogue of lisuride, decreased locomotor activity, produced cataplexy, and blocked apomorphine-induced stereotypic behavior. It did not induce stereotypies in rodents or emesis in dogs. However, in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra, terguride produced contralateral rotation. Terguride bound to D-2 striatal dopamine receptors. Terguride has both agonist and antagonist actions at striatal dopamine receptors, but chronic administration did not produce behavioral supersensitivity. These pharmacologic properties differ from those of other antiparkinsonian agents; terguride may be effective for the chronic treatment of Parkinson's disease.

Topics: Amphetamine; Animals; Apomorphine; Behavior, Animal; Brain; Disease Models, Animal; Ergolines; Levodopa; Lisuride; Male; Motor Activity; Parkinson Disease; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereotyped Behavior

Topics: Animals; Antidepressive Agents; Caffeine; Depression; Disease Models, Animal; Ergolines; Exploratory Behavior; Female; Lisuride; Male; Rats; Rats, Inbred Strains

Topics: Animals; Depression; Disease Models, Animal; Electroshock; Ergolines; Female; Male; Metergoline; Motor Activity; Nicergoline; Rats; Rats, Inbred SHR; Rats, Inbred Strains

Topics: Adjustment Disorders; Animals; Bromocriptine; Disease Models, Animal; Ergolines; Female; Imipramine; Lisuride; Male; Motor Activity; Rats; Rats, Inbred Strains

To test the hypothesis that a new potent and selective 5-HT2 receptor antagonist would be an excellent blocker of D,L-5-hydroxytryptophan (5-HTP)-induced response suppression in an animal model of depression, we administered LY53857 60 min prior to 5-HTP injections into rats working on an operant schedule for milk reinforcement. As predicted, LY53857 pretreatment significantly blocked 5-HTP depression (90%) in doses as low as 0.1 mg/kg ip. When the dose of LY58357 was further reduced to 0.025 mg/kg, blockade of 5-HTP-induced depression was still greater than 30%. In doses as high as 5.0 mg/kg, LY53857 alone had no effect on the baseline performance of rats working a VI 1 schedule. Pretreatment with desipramine (2.5 mg/kg), an antidepressant characterized as having major noradrenergic effects, did not significantly block the 5-HTP-induced depression. These data suggest that the 5-HTP-induced depression is mediated by serotonergic mechanisms involving 5-HT2 receptors, as LY53857 is a selective antagonist of these receptors. These data also support the suggestion, based on other published data from this laboratory, that some antidepressants are antagonizing 5-HT2 receptors in our animal model of depression and may also act in a similar manner in depressed patients. Thus, this new drug could be of interest as a possible antidepressant agent of the general type that was proposed earlier by Aprison and Hingtgen (1981).

Topics: 5-Hydroxytryptophan; Animals; Cerebral Cortex; Conditioning, Operant; Depression; Desipramine; Disease Models, Animal; Dose-Response Relationship, Drug; Ergolines; Humans; Male; Rats; Rats, Inbred Strains; Serotonin Antagonists

Unilateral cerebral ischaemia was induced in 18-month-old Long-Evans rats by injection of 2,000 labelled microspheres (phi 50 microns) into the carotid blood stream. This results in an ipsilateral decrease in cerebral blood flow, development of severe oedema and modifications of glucose uptake and consumption. Furthermore, this ischaemia led to a deterioration of the avoidance response in conditioned animals. All these disturbances, including the cerebral oedema, diminished with nicergoline pretreatment.

Topics: Aging; Animals; Avoidance Learning; Behavior, Animal; Brain; Brain Ischemia; Cerebrovascular Circulation; Deoxyglucose; Disease Models, Animal; Ergolines; Hemodynamics; Male; Nicergoline; Rats; Rats, Inbred Strains

According to the classification scheme of Kebabian and Calne, there are two types of dopamine (DA) receptors: D1 (activation of which causes increased cyclic AMP formation) and D2 (activation of which causes no increment in cyclic AMP). It is not clear what role the different receptors play in mediating motor behavior. Using drugs that act selectively at only one receptor site, we studied the effects of D1 and D2 receptor activation in two different models of parkinsonism--the rotating rat and the reserpinized mouse. Neither the D1 agonist nor the D2 agonist, given alone, could overcome reserpine akinesia, but together they restored locomotor activity. In rats with unilateral nigrostriatal lesions, both drugs induced a rotational response, each with a distinct temporal pattern. Pretreatment with alpha-methyl-paratyrosine (an inhibitor of DA synthesis) led to decrements in the rotational response induced by D2 agonists, but not that induced by D1 agonists. The mechanism by which these DA agonists induce motor activity is different; activation of both types of DA receptors seems to be necessary for normal motor behavior.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Benzazepines; Disease Models, Animal; Ergolines; Female; Locomotion; Mice; Mice, Inbred Strains; Parkinson Disease; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Reserpine

Topics: Animals; Disease Models, Animal; Drug Implants; Ergolines; Ethers; Male; Prolactin; Rats

Animals were administered clozapine or haloperidol for 22 days. Following treatment they were challenged with an apomorphine ester or lergotrile. Only haloperidol-treated animals exhibited significantly enhanced responses to apomorphine ester whereas administration of lergotrile potentiated locomotor activity in both treated groups. The results suggest that the use of different dopaminergic agonists may help to dissociate receptor supersensitivity arising from the antipsychotic actions of neuroleptics from that leading to the development of undesirable side effects.

Topics: Animals; Antipsychotic Agents; Apomorphine; Disease Models, Animal; Dopamine; Dyskinesia, Drug-Induced; Ergolines; Male; Motor Activity; Rats; Time Factors

Topics: Acetonitriles; Animals; Bromocriptine; Disease Models, Animal; Ergolines; Humans; Liver; Parkinson Disease; Pyridines; Structure-Activity Relationship

Studies on rats with unilateral nigral lesions suggest that a new ergoline, CF 25-397, is a dopaminergic agonist that might improve parkinsonism. CF 25-397 induces less stereotyped behavior than other dopaminergic agents in rats, and might therefore cause less dyskinesia than levodopa in man. We investigated the clinical actions of CF 25-397 in nine patients. During treatment, severe deterioration resulted in hypokinesia and rigidity; five patients showed marked dysphagia and dysphonia. There was statistically significant deterioration in four timed tests. Mild improvement, not statistically significant, was noted in tremor. These results indicate that clinical implication of the response to potential therapeutic agents in rodent models of parkinsonism must be interpreted with caution.

Topics: Aged; Animals; Corpus Striatum; Deglutition Disorders; Disease Models, Animal; Dopamine; Drug Evaluation; Drug Evaluation, Preclinical; Ergolines; Female; Humans; Male; Middle Aged; Movement Disorders; Parkinson Disease; Rats; Species Specificity; Stereotyped Behavior; Tremor

Topics: Animals; Antiparkinson Agents; Disease Models, Animal; Ergolines; Levodopa; Male; Muscle Rigidity; Rats; Urea

The antiparkinsonian activity of lergotrile mesylate, a presumed dopaminergic receptor stimulating agent, was investigating in monkeys with surgically induced tremor and in parkinsonian patients. The administration of lergotrile resulted in a dose-dependent reduction in the intensity of tremor in the monkeys. In 13 patients with Parkinson's disease treated with lergotrile (up to 12 mg a day), overall improvement was observed in five. Tremor was the main clinical feature to benefit, and the improvement reached statistical significance. In a subgroup of four patients treated with a higher dose of lergotrile (up to 20 mg a day), further improvement in rigidity and bradykinesia was noted, but again, only improvement in tremor was statistically significant. Adverse effects included orthostatic hypotension, behavioral alterations, and nausea and vomiting. These were severe enough to result in drug withdrawal in three patients.

Topics: Acetonitriles; Aged; Animals; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Drug Evaluation; Drug Evaluation, Preclinical; Ergolines; Female; Gait; Haplorhini; Humans; Male; Mesylates; Middle Aged; Muscle Rigidity; Parkinson Disease; Prolactin; Receptors, Drug; Tremor