Chronopharmacological study of antidepressants in forced swimming test of mice.
The influence of dosing time on the anti-immobility effect of antidepressants and mechanisms underlying this phenomenon were investigated in mice. In the forced swimming test (FST), the immobility time of mice treated with amitriptyline (15 mg/kg) and fluvoxamine (30 mg/kg) showed a significant 24-h rhythm. The anti-immobility effect of fluvoxamine in FST was potent at the early part of the dark phase without increasing locomotor activity. Concerning pharmacokinetics, although K(e) of fluvoxamine was approximately 1.3-fold higher in mice injected with fluvoxamine at 9:00 PM than at 9:00 AM, no dosing time dependence was demonstrated for either plasma or brain fluvoxamine concentration at 0.5 h after the drug injection. On the other hand, serotonin transporter (SERT) mRNA expression and 5-hydroxytryptamine (5-HT) uptake activity in the mouse midbrain showed significant time-dependent changes with higher levels during the dark phase and lower levels during the light phase. These results suggest that the reuptake of 5-HT might be more increased during the dark phase. Since the reuptake of 5-HT is inhibited almost completely by injection with 30 mg/kg fluvoxamine at any time, the extracellular 5-HT level may be more increased by the injection of fluvoxamine at the early part of the dark phase. The present results suggest that the anti-immobility effect of fluvoxamine in FST increases depending on dosing time. Furthermore, the time-dependent change of SERT mRNA expression and uptake activity in the midbrain is suggested to be the mechanism underlying the 24-h rhythm of anti-immobility effect of fluvoxamine.
Ushijima
Kentarou
K
Clinical Pharmacokinetics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Sakaguchi
Hiromi
H
Sato
Yuki
Y
To
Hideto
H
Koyanagi
Satoru
S
Higuchi
Shun
S
Ohdo
Shigehiro
S
D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D018687:Antidepressive Agents, Second-Generation / Q000097:blood / Q000493:pharmacokinetics; D003863:Depression / Q000188:drug therapy* / Q000523:psychology*; D004305:Dose-Response Relationship, Drug; D016666:Fluvoxamine / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013550:Swimming / Q000523:psychology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D012333:RNA, Messenger; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D012313:RNA; D016666:Fluvoxamine