Psychopharmacology

, Volume 93, Issue 1, pp 127–132 | Cite as

Evidence of strain differences in GABA-benzodiazepine coupling

  • L. Wilks
  • Sandra E. File
  • I. L. Martin
Original Investigations

Abstract

The effects of a single dose of oxazepam on seizure threshold, receptor occupancy and brain oxazepam concentration were investigated at several time points after drug treatment in two inbred strains of mice (NIH and C3H/HE). The C3H/HE strain showed a greater sensitivity to the effects of both pentylenetetrazol and oxazepam. Furthermore, the C3H/HE strain showed decreases in both receptor occupancy and seizure threshold across time, whereas the NIH strain showed no change in either measure. Although within-strain correlations were observed between seizure threshold and receptor occupancy, the C3H/HE strain had similar seizure thresholds to the NIH strain throughout but lower percentage receptor occupancies, thus a between-strain correlation was not observed. The C3H/HE strain had a higher number of specific benzodiazepine binding sites and these results may reflect a strain difference in GABA-benzodiazepine receptor coupling. In a further experiment, the development of acute tolerance to the effects of oxazepam was investigated. Brain concentrations of oxazepam and receptor occupancies were determined for each strain of mouse, at two different time points (1.5 and 7.5 h after drug treatment), at which equivalent seizure thresholds were obtained by manipulating the starting dose of oxazepam. For each strain, when equivalent seizure thresholds were observed at different time points, equivalent receptor occupancies were also observed. However, a trend towards higher brain concentrations of oxazepam at the later time point was detected for the two strains, suggesting that there may be some decrease across time in the affinity of the receptor for oxazepam.

Key words

Benzodiazepines Oxazepam Pentylenetetrazol Anticonvulsant Receptor occupancy Strain differences Mouse Acute tolerance 

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References

  1. Burt GS (1962) Strain differences in picrotoxin seizure threshold. Nature 182:301–302CrossRefGoogle Scholar
  2. Duka T, Hollt V, Herz A (1979) In vivo receptor occupation by benzodiazepines and correlation with the pharmacological effect. Brain Res 179:147–156PubMedCrossRefGoogle Scholar
  3. File SE, Greenblatt DJ, Martin IL, Brown C (1985) Long-lasting anticonvulsant effects of diazepam in different mouse strains: correlations with brain concentrations and receptor occupancy. Psychopharmacology 86:137–141PubMedCrossRefGoogle Scholar
  4. Lippa AS, Klepner CA, Yunger L, Sano MC, Smith WV, Beer B (1978) Relationships between benzodiazepine receptors and experimental anxiety in rats. Pharmacol Biochem Behav 16:529–532Google Scholar
  5. Lister RG, Abernethy DR, Greenblatt DJ, File SE (1983) Methods for the determination of lorazepam and chlordiazepoxide and metabolites in brain tissue: a comparison with plasma concentrations in the rat. J Chromatogr 277:201–208PubMedGoogle Scholar
  6. Mennini T and Garattini S (1982) Benzodiazepine Receptors: correlation with pharmacological responses in living animals. Life Sci 31:2025–2035PubMedCrossRefGoogle Scholar
  7. Paul SM, Syapin PJ, Paugh BA, Moncada V, Skolnick P (1979) Correlation between benzodiazepine receptor occupation and anticonvulsant effects of diazepam. Nature 281:688–689PubMedCrossRefGoogle Scholar
  8. Shephard RA, Neilsen EB, Broadhurst PL (1982) Sex and strain differences in benzodiazepine receptor binding in roman rat strains. Eur J Pharmacol 77:327–330PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1987

Authors and Affiliations

  • L. Wilks
    • 1
  • Sandra E. File
    • 1
  • I. L. Martin
    • 2
  1. 1.MRC Neuropharmacology Research Group, Department of Pharmacology, The School of PharmacyUniversity of LondonLondonUK
  2. 2.MRC Molecular Neurobiology UnitCambridgeUK

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