Antidepressant-like effects of the novel, selective, 5-HT2C receptor agonist WAY-163909 in rodents

Rosenzweig‐Lipson, Sharon; Sabb, Annmarie L.; Stack, Gary; Mitchell, Paul J.; Lucki, Irwin; Malberg, Jessica E.; Grauer, Steve; Brennan, Julie; Cryan, John F.; Rizzo, Stacey J. Sukoff; Dunlop, John; Barrett, James E.; Marquis, Karen L.

doi:10.1007/s00213-007-0710-6

Cited by 97 publications

(66 citation statements)

References 38 publications

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“…However, either 5-HT2C-R gene knockout or systemic treatment with the selective 5-HT2C-R antagonists SB 242084 or RS 102221 has been shown to both potentiate the antidepressant-related effects of SRIs in the tail suspension test and augment the increases in cortical and hippocampal ECF serotonin levels produced by SRI treatment (Cremers et al, 2004(Cremers et al, , 2007. On the other hand, systemic treatment with the novel 5-HT2C-R agonists WAY 163909, RO 600175 also exert antidepressant-like effects in a range of rodent assays (Cryan and Lucki, 2000;Martin et al, 1998;Rosenzweig-Lipson et al, 2007). These data have not been reconciled but they imply that the influence of genetically driven variation in human HTR2C function on risk for depression in humans may be complex.…”

Section: -Ht2c Receptorsmentioning

confidence: 99%

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Holmes

2008

Neuroscience & Biobehavioral Reviews

249

166

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The serotonin system is strongly implicated in the pathophysiology and therapeutic alleviation of stress-related disorders such as anxiety and depression. Serotonergic modulation of the acute response to stress and the adaptation to chronic stress is mediated by a myriad of molecules controlling serotonin neuron development (Pet-1), synthesis (tryptophan hydroxylase 1 and 2 isozymes), packaging (vesicular monoamine transporter 2), actions at presynaptic and postsynaptic receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3A, 5-HT4, 5-HT5A, 5-HT6, 5-HT7), reuptake (serotonin transporter), and degradation (monoamine oxidase A). A growing body of evidence from preclinical rodents models, and especially genetically modified mice and inbred mouse strains, has provided significant insight into how genetic variation in these molecules can affect the development and function of a key neural circuit between the dorsal raphe nucleus, medial prefrontal cortex and amygdala. By extension, such variation is hypothesized to have a major influence on individual differences in the stress response and risk for stress-related disease in humans. The current article provides an update on this rapidly evolving field of research.

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Section: -Ht2c Receptorsmentioning

confidence: 99%

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Holmes

2008

Neuroscience & Biobehavioral Reviews

249

166

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“…We also examined possible between-strain differences on schedule-induced polydipsia (SIP) task that has been suggested as a model of OCD (Platt et al, 2008;Rosenzweig-Lipson et al, 2007;Woods et al, 1993;Woods-Kettelberger et al, 1996). As impulsive behaviors have been related to monoaminergic dysfuctions (Winstanley et al, 2006), we assessed basal neurochemical function in the striatum and nucleus accumbens of RHA-I and RLA-I rats.…”

Section: Introductionmentioning

confidence: 99%

Impulsivity Characterization in the Roman High- and Low-Avoidance Rat Strains: Behavioral and Neurochemical Differences

Moreno

Cardona

Gómez

et al. 2010

Neuropsychopharmacol

134

106

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The selective breeding of Roman high-(RHA) and low-avoidance (RLA) rats for rapid vs extremely poor acquisition of active avoidance behavior in a shuttle-box has generated two phenotypes with different emotional and motivational profiles. The phenotypic traits of the Roman rat lines/strains (outbred or inbred, respectively) include differences in sensation/novelty seeking, anxiety/fearfulness, stress responsivity, and susceptibility to addictive substances. We designed this study to characterize differences between the inbred RHA-I and RLA-I strains in the impulsivity trait by evaluating different aspects of the multifaceted nature of impulsive behaviors using two different models of impulsivity, the delay-discounting task and five-choice serial reaction time (5-CSRT) task. Previously, rats were evaluated on a schedule-induced polydipsia (SIP) task that has been suggested as a model of obsessive-compulsive disorder. RHA-I rats showed an increased acquisition of the SIP task, higher choice impulsivity in the delay-discounting task, and poor inhibitory control as shown by increased premature responses in the 5-CSRT task. Therefore, RHA-I rats manifested an increased impulsivity phenotype compared with RLA-I rats. Moreover, these differences in impulsivity were associated with basal neurochemical differences in striatum and nucleus accumbens monoamines found between the two strains. These findings characterize the Roman rat strains as a valid model for studying the different aspects of impulsive behavior and for analyzing the mechanisms involved in individual predisposition to impulsivity and its related psychopathologies.

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“…As a consequence, it has received significant attention as a target for drug discovery. Several novel 5-HT 2C receptor agonists have been described, including [7bR,10aR)-1,2,3,4,8,9,10, 10a-octahydro-7bH-cyclopenta-[b] [1,4]diazepino [6,7,1hi]indole] (WAY-163909) (Dunlop et al, 2005;Marquis et al, 2007;Rosenzweig-Lipson et al, 2007), 2-[(3-chlorophenyl)methoxy]-6-(1-piperazinyl)pyrazine hydrochloride (CP-809101) (Siuciak et al, 2007), and lorcaserin (Thomsen et al, 2008), and shown to have activity in preclinical animal models used to evaluate potential antipsychotic, antidepressant, and antiobesity activity. Moreover, lorcaserin has demonstrated clinical efficacy in obesity (Smith et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Characterization of Vabicaserin (SCA-136), a Selective 5-Hydroxytryptamine 2C Receptor Agonist

Dunlop

Watts

Barrett

et al. 2011

J Pharmacol Exp Ther

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The 5-hydroxytryptamine 2C (5-HT 2C ) receptor subtype has received considerable attention as a target for drug discovery, having been implicated in a wide variety of disorders. Here, we describe the in vitro pharmacological profile of the novel 5-HT 2C receptor-selective agonist vabicaserin [(Ϫ)-4,5,6,7,9,9a,10, 11,12,12a-decahydrocyclopenta[c] [1,4]diazepino[6,7,1-ij]quinoline hydrochloride] (SCA-136), including a comprehensive strategy to assess 5-HT 2B receptor selectivity using diverse preparations and assays of receptor activation. Vabicaserin displaced 125 I-(2,5-dimethoxy)phenylisopropylamine binding from human 5-HT 2C receptor sites in Chinese hamster ovary cell membranes with a K i value of 3 nM and was Ͼ50-fold selective over a number of serotonergic, noradrenergic, and dopaminergic receptors. Binding affinity determined for the human 5-HT 2B receptor subtype using [ 3 H]5HT was 14 nM. Vabicaserin was a potent and full agonist (EC 50 , 8 nM; E max , 100%) in stimulating 5-HT 2C receptorcoupled calcium mobilization and exhibited 5-HT 2A receptor antagonism and 5-HT 2B antagonist or partial agonist activity in transfected cells, depending on the level of receptor expression. In rat stomach fundus and human colonic longitudinal muscle endogenously expressing 5-HT 2B receptors, vabicaserin failed to induce a 5-HT 2B receptor-dependent contraction and produced a rightward shift of the 5-HT and ␣-methyl-5-HT concentration-response curves in these preparations, respectively, consistent with 5-HT 2B competitive antagonism. Likewise, vabicaserin failed to induce a 5-HT 2B receptor-mediated contraction in arteries from deoxycorticosterone acetate-salt-treated rats, a model of hypersensitized 5-HT 2B receptor function, and produced a rightward shift in the 5-HT-induced response that was consistent with 5-HT 2B receptor antagonism. In summary, vabicaserin is a novel, potent, and selective 5-HT 2C receptor agonist.

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Antidepressant-like effects of the novel, selective, 5-HT2C receptor agonist WAY-163909 in rodents

Abstract: Taken together, these results demonstrate that the novel 5-HT2C receptor agonist WAY-163909 produces rapid onset antidepressant-like effects in animal models and may be a novel treatment for depression.

Cited by 97 publications

References 38 publications

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Impulsivity Characterization in the Roman High- and Low-Avoidance Rat Strains: Behavioral and Neurochemical Differences

Characterization of Vabicaserin (SCA-136), a Selective 5-Hydroxytryptamine 2C Receptor Agonist

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