Antiobesity-like effects of the 5-HT2C receptor agonist WAY-161503

Rosenzweig‐Lipson, Sharon; Zhang, Jean; Mazandarani, Hossein; Harrison, Boyd L.; Sabb, Annmarie L.; Sabalski, Joan; Stack, Gary; Welmaker, Greg; Barrett, James E.; Dunlop, John

doi:10.1016/j.brainres.2005.12.052

Cited by 76 publications

(59 citation statements)

References 31 publications

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“…For example, selective serotonin-reuptake transporter inhibitors including citalopram, fluxetin and sertraline are useful tools for attempting to reduce body weight in rodent models 25,26 and obese patients. 27 Apart from inhibitors of the serotoninreuptake transporter, inhibitors of the serotonin receptors 5-HT1b and 5-HT2c were found to be effective in weight reduction 28,29 and even more effective in combination with serotonin-reuptake transporter inhibitors. 30 Moreover, our data clearly show that the 5-HT3 receptor is involved.…”

Section: Discussionmentioning

confidence: 99%

Treatment with the 5-HT3 antagonist tropisetron modulates glucose-induced obesity in mice

et al. 2009

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Objective: Sugar consumption has increased markedly over the last few decades and parallels the dramatic increase in overweight and obesity. Data obtained from animal studies suggest that the intestinal serotonergic system and herein particularly the serotonin receptor 3 (5-HT3R) may be involved in sugar detection and short-term control of food intake. Using a mouse model, we tested the hypothesis that blocking 5-HT3R prevents the development of sugar-induced obesity. Design: For 8 weeks, C57BL/J6 mice were offered either water containing 30% glucose or plain water in addition to normal chow. The effect of oral treatment with the 5-HT3R antagonist, tropisetron (0.2 mg kg À1 body weight), on body weight and caloric intake was studied. Results: Total caloric intake and weight gain were significantly increased in mice fed glucose compared with the control group. Tropisetron treatment reduced intestinal motility and almost completely blocked weight gain associated with glucose feeding; however, total caloric intake was not affected. The effect of tropisetron was not associated with a decreased expression of the intestinal and hepatic glucose transporters, SGLT1 (sodium-dependent glucose cotransporter) and Glut2 (glucose transporter 2); instead, the expression of these transporters was slightly increased by the 5-HT3R antagonist. However, expressions of carbohydrate responsive element binding protein and fatty acid synthase, as well as triglyceride levels in the liver were only enhanced in mice fed glucose, but remained unchanged at the level of the control group when mice were treated concomitantly with tropisetron. At the same time, b-hydroxybutyrate dehydrogenase mRNA expression and plasma levels of ketone bodies were significantly increased. Conclusion: Our results suggest that 5-HT3R is a new target for the modulation of hepatic glucose metabolism and for the prevention of obesity.

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Section: Discussionmentioning

confidence: 99%

Treatment with the 5-HT3 antagonist tropisetron modulates glucose-induced obesity in mice

et al. 2009

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“…The antagonism of 5-HT 2C receptors by atypical antipsychotics is a potential mechanism contributing to the significant, and problematic, weight gain often observed with atypical antipsychotics, such as clozapine and olanzapine. Conversely, stimulation of the 5-HT 2C receptor is known to result in decreased food intake and body weight (Cowen et al, 1995;Dunlop et al, 2005;Rosenzweig-Lipson et al, 2006). As a result, 5-HT 2C receptor agonists may be less likely to produce an increase in body weight.…”

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confidence: 99%

“…The wide distributions of 5-HT 2C receptors and mRNA in brain (Pompeiano et al, 1994;Abramowski et al, 1995), coupled with pharmacological studies, have suggested a role for 5-HT 2C receptors in mediating a broad range of effects of 5-HT in the central nervous system. Studies have implicated the 5-HT 2C receptor in schizophrenia, depression, obsessive-compulsive disorder, anxiety, and obesity (Bos et al, 1997;Cryan and Lucki, 2000;Dunlop et al, 2005;Siuciak et al, 2005;Rosenzweig-Lipson et al, 2006).…”

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confidence: 99%

WAY-163909 [(7bR,10aR)-1,2,3,4,8,9,10,10a-Octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole]: A Novel 5-Hydroxytryptamine 2C Receptor-Selective Agonist with Preclinical Antipsychotic-Like Activity

Marquis

Sabb

Logue³

et al. 2006

J Pharmacol Exp Ther

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137

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Serotonin-2C (5-HT 2C ) receptor antagonists and agonists have been shown to affect dopamine (DA) neurotransmission, with agonists selectively decreasing mesolimbic DA. As antipsychotic efficacy is proposed to be associated with decreased mesolimbic DA neurotransmission by virtue of DA D 2 receptor antagonism, the 5-HT 2C -selective receptor agonist, WAY-163909 [(7bR,10aR)-1,2, 3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino [6,7, 1hi]indole], was evaluated in animal models of schizophrenia and in vivo microdialysis and electrophysiology to determine the effects on mesolimbic and nigrostriatal DA neurotransmission. Similar to clozapine, WAY-163909 (1.7-30 mg/kg i.p.) decreased apomorphine-induced climbing with little effect on stereotypy and no significant induction of catalepsy. WAY-163909 (0.3-3 mg/kg s.c.) more potently reduced phencyclidine-induced locomotor activity compared with d-amphetamine with no effect on spontaneous activity. WAY-163909 (1.7-17 mg/kg i. . WAY-163909 (10 mg/kg s.c.) selectively decreased extracellular levels of DA in the nucleus accumbens without affecting the striatum. Likewise, in vivo electrophysiological recordings showed a decrease in the number of spontaneously firing DA neurons in the ventral tegmental area but not in the substantia nigra with both acute and chronic (21-day) administration of WAY-163909 (1-10 mg/kg i.p.). Thus, the profile of the 5-HT 2C selective receptor agonist WAY-163909 is similar to that of an atypical antipsychotic and additionally may have rapid onset properties.

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“…7). Previous reports using overexpression systems reported that WAY-161,503 reached maximal receptor activation in Chinese hamster ovary cells and ∼80% activation levels in human embryonic kidney-293 cells, indicating that the efficacy of WAY-161,503 is generally overestimated in overexpression systems, probably owing to spare receptors (Schlag et al, 2004;Rosenzweig-Lipson et al, 2006). Partial 5-HT 2C R activation by WAY-161,503 in endogenous cells suggests that the anorexigenic effects of WAY-161,503 observed in animal studies might not reflect the full therapeutic potential of 5-HT 2C R activation on feeding.…”

Section: Discussionmentioning

confidence: 97%

“…Consequently, mice deficient for the 5-HT 2C R protein exhibit severe hyperphagia leading to diabetes and concomitant hyperglycemia and insulin resistance (Tecott et al, 1995;Heisler et al, 1998;Tecott and Abdallah, 2003). Furthermore, administration of a 5-HT 2C R (WAY-161,503) or a 5-HT 1B R (CP-94,253) preferential agonists inhibited food intake by reducing meal size and duration (Halford and Blundell, 1996;Lee and Simansky, 1997;Rosenzweig-Lipson et al, 2006;Thomsen et al, 2008;Fletcher et al, 2009;Doslikova et al, 2013). Overall, it appears that PVN neurons play an important role in the central effects of 5-HT on appetite control and express 5-HT 1B R and HT 2C R subtypes.…”

Section: Introductionmentioning

confidence: 99%

Endogenous 5-HT2C Receptors Phosphorylate the cAMP Response Element Binding Protein via Protein Kinase C-Promoted Activation of Extracellular-Regulated Kinases-1/2 in Hypothalamic mHypoA-2/10 Cells

Lauffer

Glas

Gudermann

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Serotonin 5-HT 2C receptors (5-HT 2C R) activate G q proteins and are expressed in the central nervous system (CNS). 5-HT 2C R regulate emotion, feeding, reward, or cognition and may serve as promising drug targets to treat psychiatric disorders or obesity. Owing to technical difficulties in isolating cells from the CNS and the lack of suitable cell lines endogenously expressing 5-HT 2C R, our knowledge about this receptor subtype in native environments is rather limited. The hypothalamic mHypoA-2/10 cell line was recently established and resembles appetite-regulating hypothalamic neurons of the paraventricular nucleus (PVN), where 5-HT 2C R have been detected in vivo. Therefore, we tested mHypoA-2/10 cells for endogenous 5-HT 2C R expression. Serotonin or the 5-HT 2C R preferential agonist WAY-161,503 initiated cAMP response element (CRE)-dependent gene transcription with EC 50 values of 15.5 6 9.8 and 1.1 6 0.9 nM, respectively. Both responses were blocked by two unrelated 5-HT 2C R-selective antagonists (SB-242,084, RS-102,221) but not by a 5-HT 2A R (EMD-281,014) or 5-HT 2B R (RS-127,455) antagonists. By singlecell calcium imaging, we found that serotonin and WAY-161,503 induced robust calcium transients, which were also blunted by both 5-HT 2C R antagonists. Additionally we revealed, first, that 5-HT 2C R induced CRE activation via protein kinase C (PKC)-mediated engagement of extracellular-regulated kinases-1/2 and, second, that intrinsic activity of WAY-161,503 was in the range of 0.3-0.5 compared with serotonin, defining the frequently used 5-HT 2C R agonist as a partial agonist of endogenous 5-HT 2C R. In conclusion, we have shown that hypothalamic mHypoA-2/10 cells endogenously express 5-HT 2C R and thus are the first cell line in which to analyze 5-HT 2C R pharmacology, signaling, and regulation in its natural environment.

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Antiobesity-like effects of the 5-HT2C receptor agonist WAY-161503

Cited by 76 publications

References 31 publications

Treatment with the 5-HT3 antagonist tropisetron modulates glucose-induced obesity in mice

Treatment with the 5-HT3 antagonist tropisetron modulates glucose-induced obesity in mice

WAY-163909 [(7bR,10aR)-1,2,3,4,8,9,10,10a-Octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole]: A Novel 5-Hydroxytryptamine 2C Receptor-Selective Agonist with Preclinical Antipsychotic-Like Activity

Endogenous 5-HT2C Receptors Phosphorylate the cAMP Response Element Binding Protein via Protein Kinase C-Promoted Activation of Extracellular-Regulated Kinases-1/2 in Hypothalamic mHypoA-2/10 Cells

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