PT  - JOURNAL ARTICLE
AU  - Pascal Bonaventure
AU  - Lisa Kelly
AU  - Leah Aluisio
AU  - Jonathan Shelton
AU  - Brian Lord
AU  - Ruggero Galici
AU  - Kirsten Miller
AU  - John Atack
AU  - Timothy W. Lovenberg
AU  - Christine Dugovic
TI  - Selective Blockade of 5-Hydroxytryptamine (5-HT)<sub>7</sub> Receptors Enhances 5-HT Transmission, Antidepressant-Like Behavior, and Rapid Eye Movement Sleep Suppression Induced by Citalopram in Rodents
AID  - 10.1124/jpet.107.119404
DP  - 2007 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 690--698
VI  - 321
IP  - 2
4099  - http://jpet.aspetjournals.org/content/321/2/690.short
4100  - http://jpet.aspetjournals.org/content/321/2/690.full
SO  - J Pharmacol Exp Ther2007 May 01; 321
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics