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Psychopharmacology

, Volume 97, Issue 3, pp 349–354 | Cite as

The role of the benzodiazepine receptor in mediating long-lasting anticonvulsant effects and the late-appearing reductions in motor activity and exploration

  • Sandra E. File
  • Lucy J. Wilks
  • P. S. Mabbutt
Original Investigations

Abstract

The number of head-dips, the time spent head-dipping, the number of rears and the locomotor activity of mice placed in a holeboard was reduced by lorazepam (0.25 mg/kg) 1 and 1.5 h after oral administration and these reductions were reversed by the benzodiazepine antagonist flumazenil (1 mg/kg). Activity returned to control levels at 3 and 4.5 h for head-dipping, and between 3 and 12 h for rearing and locomotor activity. However, significant late-appearing reductions were found for the number of head-dips and the time spent head-dipping (6 h) and rearing and locomotor activity (15 h) and these decreases could not be reversed by flumazenil. Similar results were found after oral administration of oxazepam (7 mg/kg). Oxazepam reduced the number of head-dips and time spent head-dipping at 1, 1.5 and 3 h and these reductions were reversed by flumazenil (1 mg/kg). Head-dipping activity returned to normal at 4.5 h. Significant reductions were also found for both measures at 1, 6 and 7.5 h and these late reductions could not be reversed by flumazenil. This suggests that the late-appearing reductions in holeboard behaviours, resulting from lorazepam or oxazepam administration to mice, is not mediated by the benzodiazepine receptor. This conclusion was supported by the results from in vivo binding, which showed no change in the % receptor occupancy 3–15 h after administration of lorazepam or oxazepam. In contrast to the holeboard behaviours, the anticonvulsant effects of the two drugs showed good correlations with receptor occupancy. The anticonvulsant effect of oxazepam (7 mg/kg) significantly decreased 1–3 h after oral administration, but thereafter a steady anticonvulsant effect was retained for up to 24 h. The anticonvulsant effect of lorazepam (0.25 mg/kg) also significantly decreased 1–3 h after administration, and thereafter remained steady for up to 15 h. At all the time-points tested, oxazepam (7 mg/kg) had a significantly greater anticonvulsant effect than lorazepam (0.25 mg/kg). This was mirrored by higher percentage receptor occupancies in cortex, hippocampus and cerebellum, from 3 to 15 h after administration.

Key words

Benzodiazepine Sedation Exploration Mouse Anticonvulsant Receptor occupancy 

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Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • Sandra E. File
    • 1
  • Lucy J. Wilks
    • 2
  • P. S. Mabbutt
    • 1
  1. 1.Psychopharmacology Research Unit, UMDS Division of PharmacologyUniversity of London, Guy's HospitalLondonUK
  2. 2.MRC Neuropharmacology Research Group, The School of PharmacyUniversity of LondonLondonUK

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