Life Sciences, Vol. 32, pp. 2033-2040 Pergamon Press Printed in the U.S.A. THE BEHAVIOURAL EFFECTS OF LORAZEPAM ARE POORLY RELATED TO ITS CONCENTRATION IN THE BRAIN Richard G. Lister , Sandra E. File and David J. Greenblatt* Department of Pharmacology, The School of Pharmacy, University of London, Brunswick Square, London WCIN lAX * Division of Clinical Pharmacology, Tufts-New England Medical Center, 171 Harrison Avenue, Boston. (Received in final form January 31, 1983) Summary The brain and plasma pharmacokinetics of lorazepam were investigated in rats that had received 5 once daily injections of Z.5 or I.Z mg/kg of the compound. The sedative effects of the drug were also assessed using a holeboard test. Thirty minutes after the final injection of 1.Z mg/kg lorazepam animals showed a similar degree of sedation to animals tested 9Z min after their final injection of 0.5 mg/kg, despite having brain concentrations of lorazepam that were 3 times higher. Four hours after 0.5 mg/kg lorazepam, when the concentration of lorazepam in the brain was very low, animals' head-dipping and locomotor activity scores were still only 60% of the controls' scores. It is concluded that brain concentrations of lorazepam are of little use in predicting the behavioural effects of the compound. Although the plasma kinetics of many benzodiazepines have been extensively reported in both animals and man (i), plasma levels of these compounds are not good predictors of their behavioural effects. After an acute overdose of a benzodiazepine, patients may be minimally sedated despite having high plasma concentrations of active compounds (2). A poor relationship between plasma concentration and behavioural effect has also been observed after an acute therapeutic dose of a benzodiazepine (3). After chronic treatment tolerance develops to the sedation and motor impairment produced by the benzodiazepines and this cannot be solely attributed to a change in plasma pharmacokinetics (4-6). Since benzodiazepines are generally administered chronically, the aim of the present study was to investigate the relationship between both brain and plasma concentrations of a benzodiazepine and its behavioural effects in animals that had received five once daily injections. Lorazepam was chosen as the benzodiazepine since it has been reported to have no active metabolites in the brain of the rat (7). 0024-3205/83/172033-08503.00/0 Copyright (c) 1983 Pergamon Press Ltd.