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Research ArticleNEUROPHARMACOLOGY

Selective Blockade of 5-Hydroxytryptamine (5-HT)7 Receptors Enhances 5-HT Transmission, Antidepressant-Like Behavior, and Rapid Eye Movement Sleep Suppression Induced by Citalopram in Rodents

Pascal Bonaventure, Lisa Kelly, Leah Aluisio, Jonathan Shelton, Brian Lord, Ruggero Galici, Kirsten Miller, John Atack, Timothy W. Lovenberg and Christine Dugovic
Journal of Pharmacology and Experimental Therapeutics May 2007, 321 (2) 690-698; DOI: https://doi.org/10.1124/jpet.107.119404
Pascal Bonaventure
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Lisa Kelly
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Leah Aluisio
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Jonathan Shelton
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Brian Lord
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Ruggero Galici
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Kirsten Miller
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John Atack
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Timothy W. Lovenberg
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Christine Dugovic
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Abstract

Evidence has accumulated supporting a role for 5-hydroxytryptamine (5-HT)7 receptors in circadian rhythms, sleep, and mood disorders, presumably as a consequence of the modulation of 5-HT-mediated neuronal activity. We hypothesized that a selective 5-HT7 receptor antagonist, (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]-pyrrolidine (SB-269970), should increase activity of 5-HT neurons and potentiate the effect of selective serotonin reuptake inhibitors (citalopram). In rats, administration of 3 mg/kg s.c. citalopram alone increased the extracellular concentration of 5-HT. This effect of citalopram on extracellular 5-HT concentration was significantly enhanced by an ineffective dose of SB-269970. Combining this dose of SB-269970 with a low dose of citalopram also resulted in a significant increase in extracellular concentration of 5-HT, suggesting a potentiation of neurochemical effects. In mice, citalopram and SB-269970 dose-dependently decreased immobility time in the tail suspension test. The dose-effect curve of citalopram was shifted leftward by coadministration of an effective dose of SB-269970. Furthermore, combining ineffective doses of citalopram and SB-269970 also resulted in a significant decrease of immobility time in the tail suspension test, suggesting potentiation of antidepressant-like effects. In rats, SB-269970 potentiated the increase of rapid eye movement (REM) latency and the REM sleep decrease induced by citalopram. SB-269970 also reversed the increase in sleep fragmentation induced by citalopram. Rat plasma and brain concentrations of citalopram were not affected by coadministration of SB-269970, arguing for a pharmacodynamic rather than a pharmacokinetic mechanism. Overall, these results indicate that selective blockade of 5-HT7 receptors may enhance the antidepressant efficacy of citalopram and may provide a novel therapy to alleviate sleep disturbances associated with depression.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.107.119404.

  • ABBREVIATIONS: 5-HT, 5-hydroxytryptamine (serotonin); SB-269970, (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]-pyrrolidine; SSRI, selective serotonin reuptake inhibitor; EEG, electroencephalogram; DA, dopamine; AUC, area under the curve; ANOVA, analysis of variance; EMG, electromyogram; NREM, nonrapid eye movement; CV%, coefficient of variation; NE, norepinephrine; Veh, vehicle; AS19, (2S)-(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino)tetralin; GR205171, 2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-(2S-phenyl-piperidin-3S-yl)-amine 2HCl; M100907, (+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol.

    • Received January 3, 2007.
    • Accepted February 20, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 368 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 368, Issue 3
1 Mar 2019
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Research ArticleNEUROPHARMACOLOGY

Selective Blockade of 5-Hydroxytryptamine (5-HT)7 Receptors Enhances 5-HT Transmission, Antidepressant-Like Behavior, and Rapid Eye Movement Sleep Suppression Induced by Citalopram in Rodents

Pascal Bonaventure, Lisa Kelly, Leah Aluisio, Jonathan Shelton, Brian Lord, Ruggero Galici, Kirsten Miller, John Atack, Timothy W. Lovenberg and Christine Dugovic
Journal of Pharmacology and Experimental Therapeutics May 1, 2007, 321 (2) 690-698; DOI: https://doi.org/10.1124/jpet.107.119404

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Research ArticleNEUROPHARMACOLOGY

Selective Blockade of 5-Hydroxytryptamine (5-HT)7 Receptors Enhances 5-HT Transmission, Antidepressant-Like Behavior, and Rapid Eye Movement Sleep Suppression Induced by Citalopram in Rodents

Pascal Bonaventure, Lisa Kelly, Leah Aluisio, Jonathan Shelton, Brian Lord, Ruggero Galici, Kirsten Miller, John Atack, Timothy W. Lovenberg and Christine Dugovic
Journal of Pharmacology and Experimental Therapeutics May 1, 2007, 321 (2) 690-698; DOI: https://doi.org/10.1124/jpet.107.119404
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