Synergistic effects of tandospirone and selective serotonin reuptake inhibitors on the contextual conditioned fear stress response in rats.
The purpose of this study was to investigate the effects of co-administration of tandospirone (a 5-HT(1A) receptor agonist) and individual selective serotonin reuptake inhibitors (SSRIs) on the contextual conditioned fear stress, using an anxiety model in rats. One day after fear conditioning, tandospirone (0.3-3 mg/kg, s.c.), paroxetine (5-20 mg/kg, i.p.), fluvoxamine (30-60 mg/kg, i.p.) and citalopram (3-30 mg/kg, i.p.) significantly inhibited the conditioned freezing in a dose-dependent manner, whereas, 14 days after fear conditioning, the anxiolytic effects of these drugs were weakened. Fourteen days after fear conditioning, co-administration of tandospirone (0.3 mg/kg, s.c.) with each SSRI [paroxetine (5 mg/kg, i.p.), fluvoxamine (30 mg/kg, i.p.) and citalopram (10 mg/kg, i.p.)], given at subeffective doses, markedly inhibited the conditioned freezing without affecting the locomotor activities and CYP3A4-related pharmacokinetic drug-drug interaction. These results elucidate the pharmacodynamic synergistic effects of tandospirone and SSRIs. Therefore, this augmentation therapy (SSRI+5-HT(1A) receptor agonist) may prove useful for some anxiety disorders.
Nishikawa
Hiroyuki
H
Department of Psychiatry, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan. hnishika@med.hokudai.ac.jp
Inoue
Takeshi
T
Izumi
Takeshi
T
Koyama
Tsukasa
T
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003213:Conditioning, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005239:Fear; D054833:Isoindoles / Q000097:blood / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000097:blood / Q000494:pharmacology*; D011743:Pyrimidines / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017366:Serotonin Receptor Agonists / Q000097:blood / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood / Q000494:pharmacology*; D013997:Time Factors
D054833:Isoindoles; D010879:Piperazines; D011743:Pyrimidines; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C055267:tandospirone