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

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Abstract

Rationale

Activation of one or more of the serotonin (5-HT) receptors may play a role in mediating the antidepressant effects of SSRIs.

Objective

The present studies were conducted to evaluate the effects of the novel 5-HT2C receptor agonist WAY-163909 in animal models of antidepressant activity (forced swim test (FST), resident–intruder, olfactory bulbectomy (BULB)), in a schedule-induced polydipsia (SIP) model of obsessive–compulsive disorder and in a model for evaluating sexual dysfunction.

Results

WAY-163909 (10 mg/kg, i.p. or s.c.) decreased immobility time in Wistar–Kyoto rats in the FST, effects that were reversed by the 5-HT2C/2B receptor antagonist SB 206553. Moreover, in Sprague-Dawley rats, the profile of WAY-163909 (decreased immobility, increased swimming) in the FST was comparable to the effects of SSRIs. Acute treatment with WAY-163909 (0.33 mg/kg, s.c.) decreased rodent aggression at doses lower than those required for decreasing total behavior. Administration of WAY-163909 (3 mg/kg, i.p.) for 5 or 21 days decreased the BULB-induced hyperactivity in rats. Additionally, acute administration of WAY-163909 (3 mg/kg, i.p.) decreased adjunctive drinking in a SIP model. The effects of WAY-163909 were reversed by the 5-HT2C/2B receptor antagonist SB 206553 and the selective 5-HT2C receptor antagonist SB 242084. Chronic administration of WAY-163909 produced deficits in sexual function at doses higher (10 mg/kg, i.p.) than those required for antidepressant-like effects in the BULB model.

Conclusions

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.

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Abbreviations

SSRI:

serotonin reuptake inhibitor

BULB:

olfactory bulbectomy

5-HT:

serotonin

FST:

forced swim test

(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]-diazepino[6,7,1hi]indole:

WAY-163909

ANOVA:

analysis of variance

SEM:

standard error of the mean

DRL:

differential reinforcement of low rate

LSD:

least significant difference

OCD:

obsessive–compulsive disorder

SIP:

schedule-induced polydipsia

SD:

Sprague-Dawley

WKY:

Wistar-Kyoto

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Acknowledgements

The authors would like to thank Menelas Pangalos and Ron Magolda for their unwavering support of 5-HT2C agonist studies.

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Authors and Affiliations

  1. Discovery Neuroscience, Wyeth Research, CN-8000, Princeton, NJ, 08543, USA

    Sharon Rosenzweig-Lipson, Jessica E. Malberg, Steve Grauer, Julie Brennan, Stacey J. Sukoff Rizzo, John Dunlop, James E. Barrett & Karen L. Marquis

  2. Chemical and Screening Sciences, Wyeth Research, CN-8000, Princeton, NJ, 08543, USA

    Annmarie Sabb & Gary Stack

  3. Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK

    Paul Mitchell

  4. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Irwin Lucki & John F. Cryan

Authors
  1. Sharon Rosenzweig-Lipson
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  2. Annmarie Sabb
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  3. Gary Stack
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  4. Paul Mitchell
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  5. Irwin Lucki
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  6. Jessica E. Malberg
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  7. Steve Grauer
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  8. Julie Brennan
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  9. John F. Cryan
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  10. Stacey J. Sukoff Rizzo
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  11. John Dunlop
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  12. James E. Barrett
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  13. Karen L. Marquis
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Correspondence to Sharon Rosenzweig-Lipson.

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Rosenzweig-Lipson, S., Sabb, A., Stack, G. et al. Antidepressant-like effects of the novel, selective, 5-HT2C receptor agonist WAY-163909 in rodents. Psychopharmacology 192, 159–170 (2007). https://doi.org/10.1007/s00213-007-0710-6

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  • DOI: https://doi.org/10.1007/s00213-007-0710-6

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