ojp ELSEVIER European Journal of Pharmacology 252 (1994) 325-328 Short communication Lack of effect of flumazenil and CGS 8216 on the anxiolytic-like properties of loreclezole Gerard R. Dawson *, Rachel Curnow, Peter Bayley, Adam Rambrldge, Mark D. Trlcklebank Merck, Sharp and Dohme Research Laboratories, Neurosctence Research Centre, Terhngs Park, Eastwtck Road, Harlow, Essex CM20 2QR, UK (Recewed 25 October 1993, rewsed MS recewed 3 December 1993, accepted 7 December 1993) Abstract Loreclezole is a novel antleplleptlc that interacts in a unique way with the GABA A receptor complex Its antlconvulsant effect in rats IS reversed by benzodlazeplne receptor partial reverse agonists, such as CGS 8216 but not by the compehtlve benzodlazeplne receptor antagonist, flumazenll (Ro 15-1788) In this study loreclezole (30 0-50 0 mg/kg l p ) was found to induce an anxlolytlc-hke effect in a rat conditioned emotional response test that was reversed neither by flumazenll (10 0 mg/kg) nor by CGS 8216 (2-phenylpyrazolo[4,3-c]qulnohn-3(5H)-one, 0 3-3 0 mg/kg) The results suggest that the anxlolytlc-hke effects of loreclezole are not mediated by the benzodlazeplne receptor Key words Loreclezole, Anxlolytlc, Flumazenll, CGS 8216, (Rat) 1. Introduction Loreclezole (R 72063, (Z)-[2-chloro-2-(2,4-dichloro- phenyl)ethenyl])-lH-1,2,4-trlazole) is a novel 'broad spectrum' antlconvulsant which inhibits seizure spread and increases seizure threshold m a range of animal models (Wauquier et al, 1990) Although the exact mechanism of actaon of the compound is unknown, an action on the GABA A receptor complex has been suggested This stems from the observation that the antlconvulsant effect of loreclezole can be reversed by some benzodlazeplne inverse receptor agonists (Ash- ton et al, 1992) However, loreclezole has neghglble affinity for the benzodlazeplne recogmtlon sate labelled by [3H]flunitrazepam (K, > 10 /zM, McKernan, per- sonal communication) and its antlconvulsant effect is insensitive to the prototyplcal benzodmzeplne receptor antagonist, flumazenll (Ro 15-1788) (Wauquier et al, 1990) Together, these results suggest that loreclezole interacts in a unique way wath the GABA A receptor Compounds that potentiate the actaon of GABA have a range of behavioural effects including anxaolysas (see File, 1984 for review) Although the antlconvulsant * Corresponding author Tel 0279 440487, fax 0279 440390 effects of loreclezole have been described in detail, little is known about its other behavloural properties Using a conditioned emotional response procedure, the present study shows that loreclezole has an anxl- olytlc-hke effect in rats that is lnsensltwe to both flumazeml and the benzodlazepine receptor partial inverse agonist CGS 8216 (2-phenylpyrazolo[4,3- c]quinohn-3(5H)-one) 2. Materials and methods 2 1 Antmals Male hooded-Lister rats (Bantln and Klngman, Hull, UK, 250-300 g) served as subjects The rats were water deprived for 225 h in each 24 h period for 2 days before and during the experiments All the animals were maintained on a 12/12 h light-dark cycle (hghts on at 07 00 h) in humidity and temperature controlled rooms 2 2 Apparatus and procedures The rats were trained on a conditioned-suppression- of-licking test in 12 standard operant chambers fitted with grid floors through which scrambled electric shock Fl~w~r ~.elen~ R V