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Research ArticleBEHAVIORAL PHARMACOLOGY

Antidepressant-Like Effects of κ-Opioid Receptor Antagonists in the Forced Swim Test in Rats

Stephen D. Mague, Andrea M. Pliakas, Mark S. Todtenkopf, Hilarie C. Tomasiewicz, Yan Zhang, William C. Stevens Jr., Robert M. Jones, Philip S. Portoghese and William A. Carlezon Jr.
Journal of Pharmacology and Experimental Therapeutics April 2003, 305 (1) 323-330; DOI: https://doi.org/10.1124/jpet.102.046433
Stephen D. Mague
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Andrea M. Pliakas
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Mark S. Todtenkopf
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Hilarie C. Tomasiewicz
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Yan Zhang
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William C. Stevens Jr.
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Robert M. Jones
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Philip S. Portoghese
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William A. Carlezon Jr.
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Abstract

We showed previously that cAMP response element-binding protein (CREB) within the nucleus accumbens (NAc) of rats regulates immobility in the forced swim test (FST), an assay used to study depression. Because CREB regulates expression of dynorphin (which acts at κ-opioid receptors) in NAc neurons, these findings raised the possibility that κ-receptors mediate immobility behaviors in the FST. Here, we report that i.c.v. administration of the κ-antagonist nor-binaltorphimine dose dependently decreased immobility in the FST, suggesting that it has antidepressant-like effects. Implicating a specific effect at κ-receptors, similar antidepressant-like effects were seen after treatment with either of two novel, structurally dissimilar κ-antagonists: 5′-guanidinonaltrindole, which was effective after i.c.v. but not systemic treatment, and 5′-acetamidinoethylnaltrindole (ANTI), which was potent and effective after systemic treatment. The behavioral effects of the κ-antagonists resembled those of tricyclic antidepressants (desipramine) and selective serotonin reuptake inhibitors (fluoxetine and citalopram). Conversely, systemic administration of the κ-agonist [5α,7α,8β]-N-methyl-N-[7-[1-pyrrolidinyl]-1-oxaspiro[4.5]dec8-yl]-benzenacetamide (U-69593) dose dependently increased immobility in the FST, consistent with prodepressant-like effects. The effects of the κ-ligands in the FST were not correlated with nonspecific effects on locomotor activity. Furthermore, the most potent and effective κ-antagonist (ANTI) did not affect the rewarding impact of lateral hypothalamic brain stimulation at a dose with strong antidepressant-like effects. These findings are consistent with the hypothesis that CREB-mediated induction of dynorphin in the NAc “triggers” immobility behavior in the FST. Furthermore, they raise the possibility that κ-antagonists may have efficacy as antidepressants, but lack stimulant or reward-related effects.

Footnotes

  • This study was funded by Grant MH63266 from the National Institute of Mental Health (to W.C.), Grant DA01533 from the National Institute on Drug Abuse (to P.S.P.), an unrestricted gift from Johnson and Johnson (to W.C.), and donations by John A. Kaneb (to W.C.).

  • DOI: 10.1124/jpet.102.046433

  • Abbreviations:
    NE
    norepinephrine
    5HT
    5-hydroxytryptamine
    DA
    dopamine
    NAc
    nucleus accumbens
    CREB
    cAMP response element-binding protein
    FST
    forced swim test
    norBNI
    nor-binaltorphimine
    GNTI
    5′-guanidinonaltrindole
    ANTI
    5′-acetamidinoethylnaltrindole
    U-69593
    (5α,7α,8β)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxaspiro[4.5]dec8-yl)-benzenacetamide
    ICSS
    intracranial self-stimulation
    DMI
    desipramine
    FLX
    fluoxetine
    COC
    cocaine
    CIT
    citalopram
    SSRI
    selective serotonin reuptake inhibitor
    ANOVA
    analysis of variance
    LSD
    least significant difference
    • Received November 1, 2002.
    • Accepted January 3, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 305 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 305, Issue 1
1 Apr 2003
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Research ArticleBEHAVIORAL PHARMACOLOGY

Antidepressant-Like Effects of κ-Opioid Receptor Antagonists in the Forced Swim Test in Rats

Stephen D. Mague, Andrea M. Pliakas, Mark S. Todtenkopf, Hilarie C. Tomasiewicz, Yan Zhang, William C. Stevens, Robert M. Jones, Philip S. Portoghese and William A. Carlezon
Journal of Pharmacology and Experimental Therapeutics April 1, 2003, 305 (1) 323-330; DOI: https://doi.org/10.1124/jpet.102.046433

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Research ArticleBEHAVIORAL PHARMACOLOGY

Antidepressant-Like Effects of κ-Opioid Receptor Antagonists in the Forced Swim Test in Rats

Stephen D. Mague, Andrea M. Pliakas, Mark S. Todtenkopf, Hilarie C. Tomasiewicz, Yan Zhang, William C. Stevens, Robert M. Jones, Philip S. Portoghese and William A. Carlezon
Journal of Pharmacology and Experimental Therapeutics April 1, 2003, 305 (1) 323-330; DOI: https://doi.org/10.1124/jpet.102.046433
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