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Psychopharmacology

, Volume 192, Issue 2, pp 159–170 | Cite as

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

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

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.

Keywords

Forced swim test Resident–intruder Olfactory bulbectomy Schedule-induced polydipsia 5-HT2C receptor agonist WAY-163909 Antidepressant Rapid onset 

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

Notes

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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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Sharon Rosenzweig-Lipson
    • 1
  • Annmarie Sabb
    • 2
  • Gary Stack
    • 2
  • Paul Mitchell
    • 3
  • Irwin Lucki
    • 4
  • Jessica E. Malberg
    • 1
  • Steve Grauer
    • 1
  • Julie Brennan
    • 1
  • John F. Cryan
    • 4
  • Stacey J. Sukoff Rizzo
    • 1
  • John Dunlop
    • 1
  • James E. Barrett
    • 1
  • Karen L. Marquis
    • 1
  1. 1.Discovery NeuroscienceWyeth ResearchPrincetonUSA
  2. 2.Chemical and Screening SciencesWyeth ResearchPrincetonUSA
  3. 3.Department of Pharmacy and PharmacologyUniversity of BathBathUK
  4. 4.Department of PsychiatryUniversity of PennsylvaniaPhiladelphiaUSA

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