European Journal of Pharmacology, 81 (1982) 655-658 Elsevier Biomedical Press Short communication BEHAVIOURAL EVIDENCE FOR PARTIAL AGONIST PROPERTIES OF RO 15-1788, A BENZODIAZEPINE RECEPTOR ANTAGONIST ROBERT DANTZER * and ALAIN PI~RIO Neurobiologie des Comportements I.N.R.A., Universitb de Bordeaux 11, 146 Rue 1~o Saignat, 33076 Bordeaux Cbdex, France Received 19 April 1982, accepted 17 May 1982 655 R. DANTZER and A. PERIO, Behavioral evidence for partial agonist properties of Ro 15-1788, a benzodiazepine receptor antagonist, European J. Pharmacol. 81 (1982) 655-658. Rats trained to discriminate pentylenetetrazol from saline had this cue antagonized by the benzodiazepine, clorazepate. Ro 15-1788 reversed the antagonism of the pentylenetetrazol cue produced by clorazepate. Similarly, Ro 15-1788 blocked the anti-conflict effect of clorazepate. Rats trained to discriminate clorazepate from saline, however, generalized this cue to Ro 15-1788. These results demonstrate that Ro 15-1788 is not a pure benzodiazepine antagonist, but has partial agonist properties. Approach-avoidance conflict Benzodiazepine antagonist Clorazepate cue Drug discrimination Pentylenetetrazol cue 1. Introduction The identification in the brain of high affinity binding sites for benzodiazepines (Squires and Braestrup, 1977) has prompted the search for en- dogenous ligands and synthetic compounds able to bind differentially to subclasses of these receptors. These studies also made it possible to identify pharmacological antagonists of the benzodiazepine receptors. A new compound, Ro 15-1788, an im- idazodiazepine derivative, has recently been dem- onstrated to be a potent and specific antagonist of benzodiazepine binding both in vitro and in vivo, to be a pharmacological antagonist in many sys- tems and to be devoid of any benzodiazepine-like activity in classical pharmacological tests for anxiolytics (Hunkeler et al., 1981). Among the many tests which are available to study drug-receptor interactions in vivo, drug cue tests are particularly useful since they constitute a pharmacologically highly specific phenomenon and, at the same time, are relatively free of many * To whom correspondence should be addressed at the above address. 0014-2999/82/0000-0000/$02.75 © 1982 Elsevier Biomedical Press of the disruptive and tolerance problems associ- ated with most psychoactive drugs (Rosecrans and Glennon, 1979). In addition, they provide a valua- ble insight into the subjective effects induced by the drug. The experiments reported here were chiefly aimed at exploring the effects of Ro 15-1788 in two drug discrimination procedures previously demonstrated to be predictive of anxiolytic activ- ity. 2. Materials and methods The drug discrimination methods used here have been described in detail elsewhere (Colpaert et al., 1976; Shearman and Lal, 1979). Testing equip- ment consisted of standard Skinner boxes fitted with 2 levers and a food tray and programmed by a mini-computer. Ten Sprague-Dawley male rats were trained to press one of the levers 15 min following a 15 mg/kg pentylenetetrazol injection and the other lever 15 min following saline injec- tion. Every tenth response (FR 10) with the ap- propriate lever resulted in the delivery of a 45 mg Noyes food pellet, while responses with the incor- rect lever had no consequences. Training sessions