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.
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.
Bonaventure
Pascal
P
Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA. pbonave1@prdus.jnj.com
Kelly
Lisa
L
Aluisio
Leah
L
Shelton
Jonathan
J
Lord
Brian
B
Galici
Ruggero
R
Miller
Kirsten
K
Atack
John
J
Lovenberg
Timothy W
TW
Dugovic
Christine
C
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001812:Blood-Brain Barrier; D015283:Citalopram / Q000493:pharmacokinetics / Q000494:pharmacology*; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D019417:Hindlimb Suspension; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010636:Phenols / Q000494:pharmacology*; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D012895:Sleep, REM / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*
D000928:Antidepressive Agents; D010636:Phenols; D011985:Receptors, Serotonin; C404922:SB 269970; D012702:Serotonin Antagonists; D013449:Sulfonamides; C104425:serotonin 7 receptor; D015283:Citalopram; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin