論文

査読有り 国際誌
2019年9月

Antidepressants with different mechanisms of action show different chronopharmacological profiles in the tail suspension test in mice.

Chronobiology international
  • Hiroshi Kawai
  • ,
  • Reiko Iwadate
  • ,
  • Takuya Ishibashi
  • ,
  • Naomi Kudo
  • ,
  • Yoichi Kawashima
  • ,
  • Atsushi Mitsumoto

36
9
開始ページ
1194
終了ページ
1207
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1080/07420528.2019.1625360

The circadian system regulates sleep/wake cycles, metabolism, mood, and other functions. It also influences medication efficacy. In this study, we studied the chronopharmacological profiles of antidepressants with various modes of action. We also investigated the effects of dosing time on the pharmacological activity of several antidepressants acting on serotonergic, noradrenergic, and/or dopaminergic neurons. C57BL/6 mice were intraperitoneally administered fluoxetine, imipramine, venlafaxine, or bupropion at 08:00 h (morning), 14:00 h (mid-day), 20:00 h (evening), or 02:00 h (mid-night). Antidepressant activity was evaluated by the tail suspension test. All antidepressants reduced immobility, and their activities varied according to the dosing time. Fluoxetine and imipramine induced relatively strong rhythms with high amplitudes. Their maximal effects were observed in the morning and evening, respectively. Venlafaxine and bupropion induced weak rhythms with maximal effects in the evening and dawn, respectively. These results suggest that the antidepressant activity is associated with circadian fluctuation, and antidepressants with different modes of action have different chronopharmacological profiles. They affect locomotor activity in animals placed in novel (unfamiliar) environments. Fluoxetine, imipramine, and venlafaxine reduced locomotor activity, whereas bupropion increased it. The effects on locomotor activity also vary with circadian rhythm, and the tested drugs showed a maximal effect during the light phase. The peak time was different from that in TST. Plasma and brain levels of all drugs were slightly higher in the morning than in the evening. The dosing time dependency of the antidepressant activity did not correlate with the sedative/stimulatory activity or tissue drug level. Therefore, these latter two factors may have only a small impact on circadian antidepressant activity fluctuations. The relative activity of the serotonergic, noradrenergic, and dopaminergic systems may determine the chronopharmacological profiles of each drug. These results suggest the possibility that drug therapy be optimized by considering the dosing time when the antidepressant activity is high and other pharmacological activities leading to adverse effects are low. Further studies using animal models of depression and in clinical settings are necessary to confirm the effects of dosing time on depressed subjects.

リンク情報
DOI
https://doi.org/10.1080/07420528.2019.1625360
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/31198056

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