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Research ArticleNEUROPHARMACOLOGY

Antidepressant-Like Behavioral Effects Mediated by 5-Hydroxytryptamine2C Receptors

John F. Cryan and Irwin Lucki
Journal of Pharmacology and Experimental Therapeutics December 2000, 295 (3) 1120-1126;
John F. Cryan
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Irwin Lucki
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Abstract

The role of the 5-HT2C receptor in mediating active behaviors in the modified rat forced swim test was examined. Three novel selective 5-HT2C receptor agonists, WAY 161503 (0.1–3.0 mg/kg), RO 60-0175 (2–20 mg/kg), and RO 60-0332 (20 mg/kg), all decreased immobility and increased swimming, a pattern of behavior similar to that which occurs with the selective serotonin reuptake inhibitor fluoxetine (5–20 mg/kg). However, the prototypical but nonselective 5-HT2C receptor agonistm-chlorophenylpiperazine (1–10 mg/kg) increased immobility scores in the forced swim test. The selective 5-HT2C receptor antagonist SB 206533 was inactive when given alone (1–20 mg/kg). However, SB 206533 (20 mg/kg) blocked the antidepressant-like effects of both WAY 161503 (1 mg/kg) and fluoxetine (20 mg/kg). The atypical antidepressant (noradrenergic α2and 5-HT2C receptor antagonist) mianserin reduced immobility and increased climbing at 30 mg/kg. At a behaviorally subactive dose (10 mg/kg), mianserin abolished the effects of WAY 161503 (1 mg/kg) on both swimming and immobility scores. Mianserin blocked the effects of fluoxetine (20 mg/kg) on swimming only; mianserin plus fluoxetine reduced immobility and induced a switch to climbing behavior, suggesting activation of noradrenergic transmission. These data exemplify the benefits of using the modified rat forced swim test, which was sensitive to serotonergic compounds and distinguished behavioral changes associated with serotonergic and noradrenergic effects. Taken together, the results strongly implicate a role for 5-HT2C receptors in the behavioral effects of antidepressant drugs.

Footnotes

  • Send reprint requests to: Dr. Irwin Lucki, Department of Psychiatry, University of Pennsylvania, 538A Clinical Research Bldg., 415 Curie Blvd., Philadelphia, PA 19104-6140. Email:lucki{at}pharm.med.upenn.edu

  • ↵1 This research was supported by U.S. Public Heath Service Grant MH 36262.

  • Abbreviations:
    5-HT
    5-hydroxytryptamine (serotonin)
    FST
    forced swim test
    SSRI
    selective serotonin reuptake inhibitor
    m-CPP
    1-(3-chlorophenyl)piperazine 1:2
    WAY 161503
    8,9-dichloro-2,3,4,4a-tetrahydro-1H,6H-pyrazino[1,2-a-]quinoxalin-5-one
    RO 60-0175
    (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine 1:1 C4H4O4
    RO 60-0332
    (S)-2-(4,4,7-trimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-methylethylamine 1:1 1:1 C4H4O4
    SB 206553
    (5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole)
    • Received March 30, 2000.
    • Accepted August 11, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 295 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 295, Issue 3
1 Dec 2000
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Research ArticleNEUROPHARMACOLOGY

Antidepressant-Like Behavioral Effects Mediated by 5-Hydroxytryptamine2C Receptors

John F. Cryan and Irwin Lucki
Journal of Pharmacology and Experimental Therapeutics December 1, 2000, 295 (3) 1120-1126;

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Research ArticleNEUROPHARMACOLOGY

Antidepressant-Like Behavioral Effects Mediated by 5-Hydroxytryptamine2C Receptors

John F. Cryan and Irwin Lucki
Journal of Pharmacology and Experimental Therapeutics December 1, 2000, 295 (3) 1120-1126;
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