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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

2007; American Society for Pharmacology and Experimental Therapeutics; Volume: 321; Issue: 2 Linguagem: Inglês

10.1124/jpet.107.119404

1521-0103

Pascal Bonaventure, Lisa A. Kelly, Leah Aluisio, Jonathan Shelton, Brian Lord, Ruggero Galici, Kirsten L. Miller, John Atack, Timothy W. Lovenberg, Christine Dugovic,

Neuroscience and Neuropharmacology Research

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-HT 7 receptor antagonist, (2 R )-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-HT 7 receptors may enhance the antidepressant efficacy of citalopram and may provide a novel therapy to alleviate sleep disturbances associated with depression.