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William J Mcbride - One of the best experts on this subject based on the ideXlab platform.
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the reinforcing actions of a Serotonin 3 Receptor agonist within the ventral tegmental area evidence for subregional and genetic differences and involvement of dopamine neurons
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Zachary A Rodd, Victoria E Gryszowka, Jamie E Toalston, Scott M Oster, Dong Ji, Richard L Bell, William J McbrideAbstract:Studies from our laboratory indicated that local perfusion of the ventral tegmental area (VTA) with a Serotonin-3 (5-HT 3 ) Receptor agonist increased dopamine (DA) neuronal activity and that the self-infusion of ethanol (EtOH) and cocaine into the posterior VTA could be inhibited with coadministration of a 5-HT 3 Receptor antagonist. The study tested the hypothesis that activating 5-HT 3 Receptors within the VTA produces reinforcing effects. The study also examined whether there were differences between Wistar rats and a line of rats selectively bred for high alcohol consumption with regard to the self-infusion of a 5-HT 3 Receptor agonist within the VTA. Adult female alcohol-preferring (P) and Wistar rats were allowed to self-infuse the 5-HT 3 Receptor agonist 1-( m -chlorophenyl)-biguanide (CPBG) into the posterior or anterior VTA. Furthermore, experiments examined the effects of coinfusion of the 5-HT 3 antagonist ICS 205,930 (ICS), and the DA D 2,3 agonist quinpirole on the self-infusion of CPBG. Both Wistar and P rats readily self-administered CPBG into the posterior, but not anterior, VTA. P rats self-infused lower concentrations of CPBG (0.10 μM) than did Wistar rats (1.0 μM). Coinfusion of either ICS or quinpirole reduced CPBG self-infusion into the posterior VTA. The results of this study suggest that activation of 5-HT 3 Receptors within the posterior VTA produces reinforcing effects and that these reinforcing effects are mediated through activation of DA neurons. Furthermore, the data suggest that selective breeding for alcohol-preference results in the posterior VTA being more sensitive to the reinforcing effects of CPBG.
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effects of Serotonin 3 Receptor antagonists on the intracranial self administration of ethanol within the ventral tegmental area of wistar rats
Psychopharmacology, 2003Co-Authors: Zachary A Roddhenricks, David L Mckinzie, Roberto I Melendez, Nada Berry, James M Murphy, William J McbrideAbstract:Abstract Rationale. Previous work from our laboratory indicated that Wistar rats will self-administer ethanol (EtOH) directly into the posterior ventral tegmental area (VTA) and that 5-HT3 antagonists will inhibit EtOH-stimulated somatodendritic release of dopamine within the VTA. Objectives. The objective of this study was to use the intracranial self-administration procedure to determine the involvement of 5-HT3 Receptors in mediating the reinforcing effects of EtOH within the VTA, and to increase our understanding of central nervous system mechanisms involved in the rewarding effects of EtOH. Methods. Adult female Wistar rats were stereotaxically implanted with guide cannulae aimed at the posterior VTA. After 1 week, rats were placed into standard two-lever experimental chambers for a total of seven sessions (4-h sessions separated by 48 h) and allowed to self-administer vehicle alone, a 5-HT3 antagonist alone, 200 mg% EtOH alone, or combinations of 200 mg% EtOH with different concentrations of a 5-HT3 antagonist (n=6–9 per group). Results. Throughout all seven sessions, Wistar rats self-infused more 200 mg% ETOH (25±5 infusions) than vehicle (5±4 infusions) or 5-HT3 antagonist (6±4 infusions) (P<0.05), and responded significantly more (P<0.05) on the active than inactive lever (e.g., 50±12 vs 12±8 responses in session 1). Co-administration of 50 µM or 100 µM ICS 205,930 with 200 mg% EtOH completely prevented the acquisition and maintenance of EtOH self-infusion into the posterior VTA. Similarly, co-administration of either 25–100 µM LY-278–584 or 10–100 µM zacopride with 200 mg% EtOH completely blocked EtOH-maintained intracranial self-administration behavior. Conclusions. The results of this study suggest that the reinforcing effects of EtOH within the posterior VTA of Wistar rats require activation of local 5-HT3 Receptors.
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Effects of Serotonin-3 Receptor antagonists on the intracranial self-administration of ethanol within the ventral tegmental area of Wistar rats
Psychopharmacology, 2002Co-Authors: Zachary A. Rodd-henricks, David L Mckinzie, Roberto I Melendez, Nada Berry, James M Murphy, William J McbrideAbstract:Abstract Rationale. Previous work from our laboratory indicated that Wistar rats will self-administer ethanol (EtOH) directly into the posterior ventral tegmental area (VTA) and that 5-HT3 antagonists will inhibit EtOH-stimulated somatodendritic release of dopamine within the VTA. Objectives. The objective of this study was to use the intracranial self-administration procedure to determine the involvement of 5-HT3 Receptors in mediating the reinforcing effects of EtOH within the VTA, and to increase our understanding of central nervous system mechanisms involved in the rewarding effects of EtOH. Methods. Adult female Wistar rats were stereotaxically implanted with guide cannulae aimed at the posterior VTA. After 1 week, rats were placed into standard two-lever experimental chambers for a total of seven sessions (4-h sessions separated by 48 h) and allowed to self-administer vehicle alone, a 5-HT3 antagonist alone, 200 mg% EtOH alone, or combinations of 200 mg% EtOH with different concentrations of a 5-HT3 antagonist (n=6–9 per group). Results. Throughout all seven sessions, Wistar rats self-infused more 200 mg% ETOH (25±5 infusions) than vehicle (5±4 infusions) or 5-HT3 antagonist (6±4 infusions) (P
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Serotonin3 Receptor antagonism of alcohol intake: effects of drinking conditions.
Alcohol, 1998Co-Authors: David L Mckinzie, William J Mcbride, James M Murphy, Robert B. Stewart, L. Lumeng, Ting-kai LiAbstract:Abstract McKINZIE, D. L., R. EHA, R. COX, R. B. STEWART, W. DYR, J. M. MURPHY, W. J. McBRIDE, L. LUMENGAND T.-K. LI. Serotonin 3 Receptor antagonism of alcohol intake: Effects of drinking conditions. ALCOHOL 15 (4) 291–298, 1998.—The effects of 5-HT 3 Receptor antagonists on ethanol intake were examined in the selectively bred alcohol-preferring P line of rats under continuous and limited access to 10% (v/v) ethanol with food and water ad lib. Single daily injections of either MDL 72222 (MDL) or ICS 205-930 (ICS) (0.01–3.0 mg/kg, SC) given 60 min before a 4-h scheduled access period for 4 consecutive days failed at all doses to alter the intake of a 10% (v/v) ethanol solution by P rats. However, multiple daily injections of either MDL (1–3 mg/kg, SC) or ICS (3.0 and 5.0 mg/kg, SC), given three times daily at 4-h intervals, significantly reduced ethanol intake under 24-h free-choice conditions on the first treatment day. Additionally, a single administration of 1.0 mg/kg MDL reduced 24-h free-choice ethanol intake by approximately 50% of control values and had no effect on 24-h saccharin intake. The effects of MDL were further examined in a 2-h schedule access paradigm in which rats received the access period at the same time every day (Fixed) or randomly during the dark cycle (Variable). Although 1.0 mg/kg MDL had little effect on ethanol drinking in the Fixed group, ethanol intake was reduced by 55% of control levels in the Variable group. Overall, the data indicate that drinking conditions influence the effectiveness of 5-HT 3 antagonists to reduce ethanol consumption. Furthermore, the results suggest that conditions, associated with limited access ethanol drinking, markedly reduce the actions of 5-HT 3 antagonists on ethanol intake.
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Serotonin 3 Receptor and ethanol stimulated somatodendritic dopamine release
Alcohol, 1996Co-Authors: A D Campbell, R R Kohl, William J McbrideAbstract:The effects of local application of the 5-HT3 Receptor agonist, 1-(m-chlorophenyl)-biguanide (CPBG), and IP administration of ethanol on the extracellular levels of dopamine (DA) in the ventral tegmental area (VTA) were studied using in vivo microdialysis. Adult female Wistar rats were implanted with microdialysis probes in the VTA at least 24 h before each experiment. Stable extracellular levels of DA (101 ± 9 fmol/20 min) were established before initiating the experiments. Application of 10–250 μM CPBG through the microdialysis probe dosedependently enhanced the extracellular concentrations of DA but did not alter the levels of either 3,4-dihydroxyphenylacetic acid or homovanillic acid in the dialysate. The effects of CPBG were reversible and dependent upon Ca2+. Co-perfusion with the 5-HT3 Receptor antagonist, 3-tropanyl-indole-3-carboxylate (ICS 205-930), inhibited the effects of CPBG on enhancing extracellular DA levels. The IP administration of 2g/kg ethanol significantly (p < 0.005) enhanced the levels of DA to 150% of baseline values; this ethanol-induced increase was prevented by local perfusion with 100 μM ICS 205–930. These results suggest that 5-HT3 Receptors in the VTA are involved in regulating the somatodendritic release of DA and in mediating the stimulatory effects of ethanol on this neuronal system.
Nathorn Chaiyakunapruk - One of the best experts on this subject based on the ideXlab platform.
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Cost-effectiveness analysis of olanzapine-containing antiemetic therapy for managing highly emetogenic chemotherapy in Southeast Asia: a multinational study
Supportive Care in Cancer, 2019Co-Authors: Suthan Chanthawong, Suphat Subongkot, Alexandre Chan, Rizka Andalusia, Ros Suzanna Ahmad Bustamam, Nathorn ChaiyakunaprukAbstract:Purpose Recent studies suggested that olanzapine, together with dexamethasone and Serotonin-3 Receptor antagonist (5HT3RA), is effective in preventing chemotherapy-induced nausea and vomiting (CINV) following highly emetogenic chemotherapy (HEC). This regimen is particularly useful in Southeast Asia (SEA) countries where resources are limited. We aimed to evaluate the cost-effectiveness of incorporating olanzapine into standard antiemetic regimens for the prevention of CINV in patients receiving HEC among SEA countries. Methods Using a decision tree model, clinical and economic outcomes associated with olanzapine-containing regimen and standard antiemetic regimen (doublet antiemetic regimen: dexamethasone+first generation 5HT3RA) in most SEA countries except in Singapore (triplet antiemetic regimen: dexamethasone+first generation 5HT3RA + aprepitant) for CINV prevention following HEC were evaluated. This analysis was performed in Thailand, Malaysia, Indonesia, and Singapore, using societal perspective method with 5-day time horizon. Input parameters were derived from literature, network meta-analysis, government documents, and hospital databases. Outcomes were incremental cost-effectiveness ratio (ICER) in USD/quality-adjusted life year (QALY) gained. A series of sensitivity analyses including probabilistic sensitivity analysis were also performed. Results Compared to doublet antiemetic regimen, addition of olanzapine resulted in incremental QALY of 0.0022–0.0026 with cost saving of USD 2.98, USD 27.71, and USD 52.20 in Thailand, Malaysia, and Indonesia, respectively. Compared to triplet antiemetic regimen, switching aprepitant to olanzapine yields additional 0.0005 QALY with cost saving of USD 60.91 in Singapore. The probability of being cost-effective at a cost-effectiveness threshold of 1 GDP/capita varies from 14.7 to 85.2% across countries. Conclusion The use of olanzapine as part of standard antiemetic regimen is cost-effective for the prevention of CINV in patients receiving HEC in multiple SEA countries.
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Cost-effectiveness analysis of olanzapine-containing antiemetic therapy for managing highly emetogenic chemotherapy in Southeast Asia: a multinational study
Supportive Care in Cancer, 2018Co-Authors: Suthan Chanthawong, Suphat Subongkot, Alexandre Chan, Rizka Andalusia, Ros Suzanna Ahmad Bustamam, Nathorn ChaiyakunaprukAbstract:Recent studies suggested that olanzapine, together with dexamethasone and Serotonin-3 Receptor antagonist (5HT3RA), is effective in preventing chemotherapy-induced nausea and vomiting (CINV) following highly emetogenic chemotherapy (HEC). This regimen is particularly useful in Southeast Asia (SEA) countries where resources are limited. We aimed to evaluate the cost-effectiveness of incorporating olanzapine into standard antiemetic regimens for the prevention of CINV in patients receiving HEC among SEA countries. Using a decision tree model, clinical and economic outcomes associated with olanzapine-containing regimen and standard antiemetic regimen (doublet antiemetic regimen: dexamethasone+first generation 5HT3RA) in most SEA countries except in Singapore (triplet antiemetic regimen: dexamethasone+first generation 5HT3RA + aprepitant) for CINV prevention following HEC were evaluated. This analysis was performed in Thailand, Malaysia, Indonesia, and Singapore, using societal perspective method with 5-day time horizon. Input parameters were derived from literature, network meta-analysis, government documents, and hospital databases. Outcomes were incremental cost-effectiveness ratio (ICER) in USD/quality-adjusted life year (QALY) gained. A series of sensitivity analyses including probabilistic sensitivity analysis were also performed. Compared to doublet antiemetic regimen, addition of olanzapine resulted in incremental QALY of 0.0022–0.0026 with cost saving of USD 2.98, USD 27.71, and USD 52.20 in Thailand, Malaysia, and Indonesia, respectively. Compared to triplet antiemetic regimen, switching aprepitant to olanzapine yields additional 0.0005 QALY with cost saving of USD 60.91 in Singapore. The probability of being cost-effective at a cost-effectiveness threshold of 1 GDP/capita varies from 14.7 to 85.2% across countries. The use of olanzapine as part of standard antiemetic regimen is cost-effective for the prevention of CINV in patients receiving HEC in multiple SEA countries.
Amos D Korczyn - One of the best experts on this subject based on the ideXlab platform.
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use of the selective Serotonin 3 Receptor antagonist ondansetron in the treatment of neuroleptic induced tardive dyskinesia
American Journal of Psychiatry, 2000Co-Authors: Pinkhas Sirota, Tanya Mosheva, Hertzel Shabtay, Nir Giladi, Amos D KorczynAbstract:OBJECTIVE: The authors examined the efficacy, tolerability, and safety of ondansetron, a selective Serotonin 3 Receptor antagonist, in patients with tardive dyskinesia. METHOD: Twenty patients with schizophrenia who had neuroleptic-induced tardive dyskinesia were given 12 mg/day of ondansetron for 12 weeks in an open-label study. RESULTS: Administration of ondansetron resulted in a statistically significant improvement in tardive dyskinesia and psychotic symptoms. CONCLUSIONS: Ondansetron may be an effective and safe therapy to control tardive dyskinesia and psychosis in patients with schizophrenia.
Hisashi Takasugi - One of the best experts on this subject based on the ideXlab platform.
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new 5 ht3 Serotonin 3 Receptor antagonists iv synthesis and structure activity relationships of azabicycloalkaneacetamide derivatives
Chemical & Pharmaceutical Bulletin, 1995Co-Authors: Masayuki Kato, Shigetaka Nishino, Hisashi Yamakuni, Hisashi TakasugiAbstract:The synthesis and structure-activity relationships of a series of new azabicycloalkanes as 5-HT3 (Serotonin-3) Receptor antagonists are described. Our study on the azabicycloalkaneacetamide derivatives showed that 2, 3-dihydroindole as the aromatic ring moiety afforded potent 5-HT3 Receptor antagonist activity, as judged by blockade of bradycardia induced by i.v. injection of 2-methylSerotonin in anesthetized rats. 7-Azaindole as the aromatic moiety afforded weak 5-HT3 Receptor antagonists activity. The best 5-HT3 antagonists in this study were endo-3, 3-diethyl- (9k) and 3, 3-dimethyl-2, 3-dihydro-1-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)acetyl-1H-indole (9d), being approximately 10-fold more potent than ondansetron (1). This study shows that the azabicycloalkaneacetyl group is a new pharmacophoric element as a basic nitrogen and a linking carbonyl moiety.
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New 5-HT3 (Serotonin-3) Receptor antagonists. V: Synthesis and structure-activity relationships of pyrrolo[2,1-c][1,4]benzoxazine-6-carboxamides
Chemical & Pharmaceutical Bulletin, 1995Co-Authors: Masayuki Kato, Shigetaka Nishino, Hisashi Yamakuni, Hisashi TakasugiAbstract:This paper describes the discovery of structurally novel heterocyclic carboxamides which are highly potent 5-HT3 (Serotonin-3) Receptor antagonists. Pyrrolo[2, 1-c][1, 4]benzoxazine-6-carboxamides (12 and 20) were found to possess potent 5-HT3 Receptor antagonist activity on the von Bezold-Jarisch reflex in anesthetized rats. Structure-activity studies showed that compounds with small and lipophilic substituents such as chloro and methyl at the 8-position of the aromatic ring portion retained high potency, whereas those with bulky substituents showed essentially no activity. A dimethyl group at the 4-position slightly decreased the potency. 1-Azabicyclo[2.2.2]octan-3-amine as the amine part afforded the most potent activity. From this series, 20a was found to be the most potent 5-HT3 Receptor antagonist, being 40-fold more potent than ondansetron (1).
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New 5-HT3 (Serotonin-3) Receptor antagonists. III. An efficient synthesis of carbon 14-labeled (+)-8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4- yl)methyl]pyrido[1,2-a]indol-6(7H)-one hydrochloride (FK 1052).
Chemical & Pharmaceutical Bulletin, 1995Co-Authors: Masayuki Kato, Shigetaka Nishino, Hisashi TakasugiAbstract:(+)-8, 9-Dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1, 2-a]indol-6(7H)-one hydrochloride (FK 1052, 1) is a highly poten 5-HT3 (Serotonin-3) Receptor antagonist. For the study of the metabolism and disposition of FK 1052 (1), we synthesized carbon 14-labeled FK 1052 in three steps from 10-demethyl FK 1052 (8). The Mannich reaction and subsequent hydrogenolysis of the dimethylaminomethyl group enabled the efficient introduction of one carbon atom at the 10-position of the pyrido[1, 2-a]indol-6(7H)-one ring. The Mannich reaction of (+)-8, 9-dihydro-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1, 2-a]indol-6(7H)-one (8) with [14C]paraformaldehyde and dimethylamine hydrochloride gave the [14C]-10-dimethylaminomethyl compound (20). Subsequent hydrogenolysis of 20 with palladium on carbon and ammonium formate, followed by recrystallization of the salt with (+)-di-p-toluoyl-D-tartaric acid, gave[14C]FK 1052 with a radiochemical purity of 99.4% and an enantiomeric excess of more than 97%.
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new 5 ht3 Serotonin 3 Receptor antagonists i synthesis and structure activity relationships of pyrido 1 2 a indoles
Chemical & Pharmaceutical Bulletin, 1994Co-Authors: Masayuki Kato, Shigetaka Nishino, Hisashi Yamakuni, Hisashi TakasugiAbstract:A series of pyrido[1, 2-α]indol-6(7H)-ones was prepared and evaluated for 5-HT3 Receptor antagonist activity. The structural requirements for the 5-HT3 Receptor antagonist have been defined as an aromatic moiety, a basic nitrogen, and a linking acyl group. The (5-methylimidazol-4-yl)methyl group as a basic nitrogen moiety was an important element for high potency. The highest potency was observed for compounds which have 7- and 10-methyl substituents on the pyrido[1, 2-α]indol-6(7H)-one ring. From this series, (+)-11b (FK 1052) was selected for further evaluation. FK 1052 was a potent 5-HT3 Receptor antagonist in the Bezold-Jarisch reflex test in rats (ED50 0.9 μg/kg, i.v.) and a very effective antiemetic agent against cisplatin-induced emesis in dogs (ED50 1.1×2 μg/kg, i.v. and 2.7×2 μg/kg, p.o.).
Nakao Iwata - One of the best experts on this subject based on the ideXlab platform.
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Selective Serotonin 3 Receptor Antagonist Treatment for Schizophrenia: Meta-analysis and Systematic Review
NeuroMolecular Medicine, 2014Co-Authors: Taro Kishi, Tomohiko Mukai, Yuki Matsuda, Nakao IwataAbstract:Double-blinded, randomized, placebo-control trials of selective Serotonin 3 Receptor antagonists (5-HT_3R-ANTs) for schizophrenia have differed in outcome. This meta-analysis tests the hypothesis that 5-HT_3R-ANTs are effective for the treatment for schizophrenia. We searched PubMed, the Cochrane Library database, and PsycINFO up to June 15, 2013. We conducted a systematic review and meta-analysis of individual patient data from randomized controlled trials comparing 5-HT_3R-ANTs add-on therapy with placebo. The risk ratio (RR), 95 % confidence intervals (CI), and standardized mean difference (SMD) were calculated. A random-effects model was used. Six studies (total n = 311) were identified. These included one granisetron plus risperidone study, one ondansetron plus risperidone study, one ondansetron plus haloperidol, and three tropisetron plus risperidone studies. The statistically significant effects of 5-HT_3R-ANTs add-on therapy on Positive and Negative Syndrome Scale (PANSS) total scores were SMD = −1.03, CI = −1.70 to −0.36, p = 0.003 ( I ^2 = 82 %, 5 studies, n = 261); on negative scores were SMD = −1.10, CI = −1.82 to −0.39, p = 0.002 ( I ^2 = 84 %, 5 studies, n = 261); and on PANSS general scores were SMD = −0.70, CI = −1.23 to −0.17, p = 0.01 ( I ^2 = 73 %, 5 studies, n = 261). However, 5-HT_3R-ANTs add-on therapy was not superior to placebo in PANSS positive scores (SMD = −0.12, p = 0.33). Dropout due to all cause (RR = 0.80, p = 0.50), inefficacy (RR = 0.76, p = 0.65), or adverse events (RR = 0.84, p = 0.75) was similar in both groups. Constipation occurred significantly more often with 5-HT_3R-ANTs than placebo (RR = 2.05, CI = 1.07–3.91, p = 0.03, NNH = 11, p = 0.02). 5-HT_3R-ANTs add-on therapy is more beneficial on the psychopathology (especially negative symptoms) than controls in patients with schizophrenia, and 5-HT_3R-ANTs seem to be well-tolerated treatments.
