Abstract
After 3 days of dosing rats with lorazepam (0.25 mg/kg), tolerance developed to its sedative effects. Recovery from this tolerance was rapid. No differences could be detected in undrugged behaviour 24 h after the last dose and no differences in response to a probe injection could be found when 2 drug-free days intervened between the chronic treatment and test dose. RO 15-1788 (1–4 mg/kg) antagonised the sedative effects of acute lorazepam (0.5 and 0.25 mg/kg), but chronic treatment with these doses concomitantly with lorazepam did not prevent the development of tolerance. However, 4 mg/kg RO 15-1788 administered for 5 days at the same time as lorazepam (0.5 mg/kg) and again 45 min later attenuated the development of tolerance. Plasma concentrations after acute and chronic treatment did not differ for 0.25 mg/kg lorazepam, but they were lower following chronic treatment with 0.5 mg/kg. Therefore the development of behavioural tolerance in rats to the sedative effects of benzodiazepines probably involves changes in benzodiazepine receptors, in addition to a pharmacokinetic contribution after treatment with high doses.
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References
Braestrup C, Nielsen M, Squires RF (1979) No changes in rat benzodiazepine receptors after withdrawal from continuous treatment with lorazepam and diazepam. Life Sci 24:347–350
Cook L, Sepinwall J (1975) Behavioral analysis of the effects and mechanisms of action of benzodiazepines. In: Costa E, Greengard P (eds) Mechanisms of action of benzodiazepines. Raven, New York, pp 1–28
Duncan DB (1955) Multiple range and multiple F tests. Biometrics 11:1–42
File SE (1981) Rapid development of tolerance to the sedative effects of lorazepam and triazolam in rats. Psychopharmacology 73:240–245
File SE, Hyde JRG (1978) Can social interaction be used to measure anxiety?. Br J Pharmacol 62:19–24
File SE, Wardill AG (1975a) The reliability of the holeboard apparatus. Psychopharmacologia 44:47–51
File SE, Wardill AG (1975b) Validity of head-dipping as a measure of exploration in a modified holeboard. Psychopharmacologia 44:53–59
Greenblatt DJ, Franke K, Shader RI (1978) Analysis of lorazepam and its glucuronide metabolite by electron-capture gas-liquid chromatography. J Chromatography 146:311–320
Greenblatt DJ, Shader RI (1974) Benzodiazepines in clinical practice. Raven, New York
Hunkeler W, Mohler H, Pieri L, Polc P, Bonetti EP, Cumin R, Schaffner R, Haefely W (1981) Selective antagonists of benzodiazepines. Nature 290:514–516
Lloyd KG, Bovier P, Broekkamp CL, Worms P (1981) Reversal of the antiaversive and anticonvulsant actions of diazepam, but not of progabide, by a selective antagonist of the benzodiazepine receptors. Eur J Pharmacol 7:77–78
Mohler H, Okada T, Enna SJ (1978) Benzodiazepine and neurotransmitter receptor binding in rat brain after chronic adminsstration of diazepam and phenobarbital. Brain Res 156:391–395
Nutt DJ, Cowen PJ, Little HJ (1982) Unusual interactions of benzodiazepine receptor antagonists. Nature 295:436–438
Rosenberg HC, Chiu TH (1979) Decreased 3H-diazepam binding is a specific response to chronic benzodiazepine treatment. Life Sci 24:803–808
Rosenberg HC, Chiu TH (1981) Tolerance during chronic benzodizzepine treatment associated with decreased receptor binding. Eur J Pharmacol 70:453–460
Stein L, Berger BD (1971) Psychopharmacology of 7-chloro-5-(O-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one (lorazepam) in squirrel, monkey and rat. Arzneim Forsch 21:1073–1078
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File, S.E. Recovery from lorazepam tolerance and the effects of a benzodiazepine antagonist (RO 15-1788) on the development of tolerance. Psychopharmacology 77, 284–288 (1982). https://doi.org/10.1007/BF00464581
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DOI: https://doi.org/10.1007/BF00464581