Inhibitory action of brotizolam on circadian and light-induced Per1 and Per2 expression in the hamster suprachiasmatic nucleus

Shin Ichi Yokota, Kazumasa Horikawa, Masashi Akiyama, Takahiro Moriya, Shizufumi Ebihara, Goyo Komuro, Tatsuro Ohta, Shigenobu Shibata

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1. Triazolam reportedly causes phase advances in hamster wheel-running rhythm after injection during subjective daytime. However, it is unclear whether benzodiazepine affects the Per gene expression accompanying a behavioural phase shift. 2. Brotizolam (0.5-10 mg kg-1) induced large phase advances in hamster rhythm when injected during mid-subjective daytime (circadian time 6 or 9), but not at circadian time 0, 3 or 15. 3. Brotizolam (5 mg kg-1) significantly reduced the expression of Per1 and Per2 in the suprachiasmatic nucleus 1 and 2 h after injection at circadian time 6, and slightly reduced them at circadian time 20. 4. Injection of 8-OH-DPAT (5 mg kg-1) at subjective daytime induced similar phase advances with a reduction of Per1 and Per2 expression. Co-administration of brotizolam with 8-OH DPAT failed to potentiate the 8-OH DPAT-induced phase advances and reduced Per expression. 5. Both phase advance and rapid induction of Per1 and Per2 in the suprachiasmatic nucleus after light exposure (5 lux, 15 min) at circadian time 20 was strongly attenuated by co-treatment with brotizolam 5 mg kg-1. 6. The present results strongly suggest that reduction of Per1 and/or Per2 expression during subjective daytime by brotizolam may be an important step in causing a behavioural phase advance. The co-administration experiment suggests that common mechanism(s) are involved in brotizolamor 8-OH DPAT-induced phase advances and the reduction of Per gene expression. 7. These results suggest that brotizolam is not only a good drug for insomnia but also a drug capable of facilitating re-entrainment like melatonin.

Original languageEnglish
Pages (from-to)1739-1747
Number of pages9
JournalBritish Journal of Pharmacology
Issue number8
Publication statusPublished - 2000 Jan 1



  • Benzodiazepine
  • Brotizolam
  • Hamster
  • Per genes
  • Phase shift
  • Suprachiasmatic nucleus

ASJC Scopus subject areas

  • Pharmacology

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