The 5-HT(7) receptor as a mediator and modulator of antidepressant-like behavior.
The 5-HT(7) receptor has been suggested as a target for treating depression since inactivation or blockade of the receptor has an antidepressant-like behavioral effect. The present study investigated possible interactions between various classes of drugs with antidepressant properties and blockade or inactivation of the 5-HT(7) receptor. Immobility despair in the tail suspension test and the forced swim test was evaluated in mice lacking the 5-HT(7) receptor (5-HT(7)(-/-)) and in wild-type controls (5-HT(7)(+/+)) following acute drug treatments. Citalopram, a selective serotonin reuptake inhibitor and widely used antidepressant, dose-dependently reduced immobility in the tail suspension test in both 5-HT(7)(+/+) and 5-HT(7)(-/-) mice. Combining doses of citalopram and the 5-HT(7) receptor antagonist SB-269970 that by themselves did not affect behavior, reduced immobility in 5-HT(7)(+/+) mice in both the tail suspension test and the forced swim test. No effect was seen in 5-HT(7)(-/-) mice. Desipramine and reboxetine, two norepinephrine reuptake inhibitors, dose-dependently reduced immobility in the tail suspension test in 5-HT(7)(+/+) mice, but had no effect in 5-HT(7)(-/-) mice. A synergistic effect between desipramine and SB-269970 was found in both behavioral tests in 5-HT(7)(+/+) mice. Reboxetine combined with SB-269970 had effect only in the forced swim test. GBR 12909, a dopamine reuptake inhibitor, dose-dependently reduced tail suspension test immobility in both genotypes. There was no interaction between GBR 12909 and SB-269970. Aripiprazole, an antipsychotic, reduced immobility in both tests in 5-HT(7)(+/+) mice, but not in 5-HT(7)(-/-) mice. The results show that the 5-HT(7) receptor is required for the observed interaction between this receptor and antidepressants such as citalopram. The data furthermore support the hypothesis that the 5-HT(7) receptor might be a suitable target for treating depression.
Sarkisyan
Gor
G
Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. gor@scripps.edu
Roberts
Amanda J
AJ
Hedlund
Peter B
PB
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology; D000068180:Aripiprazole; D015283:Citalopram / Q000494:pharmacology*; D003345:Corticosterone / Q000097:blood; D003863:Depression / Q000235:genetics; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D019417:Hindlimb Suspension / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D010636:Phenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000172:deficiency / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013550:Swimming / Q000523:psychology
D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D018765:Dopamine Uptake Inhibitors; D010636:Phenols; D010879:Piperazines; D015363:Quinolones; D011985:Receptors, Serotonin; C404922:SB 269970; D012702:Serotonin Antagonists; D013449:Sulfonamides; C104425:serotonin 7 receptor; D015283:Citalopram; D000068180:Aripiprazole; D003345:Corticosterone