DOPAMINE D-4 RECEPTOR AND ANXIETY - BEHAVIORAL PROFILES OF CLOZAPINE,L-745,870 AND L-741,742 IN THE MOUSE PLUS-MAZE

The dopamine D-4 receptor has been implicated in the therapeutic effec ts of the atypical antipsychotic, clozapine. As it has been proposed t hat anxiolytic-like activity may contribute to the efficacy of this ag ent in ameliorating the negative symptoms of schizophrenia, the curren t study employed ethological methods to fully characterize the acute b ehavioural profiles of clozapine and two more selective dopamine D-4 r eceptor antagonists, L-745,870 )piperazin-1-yl)]methyl)-1H-pyrrolo[2,3 b]pyridine) and L-741,742 hyl-3-(1-(2-phenylethyl)piperidin-4-yl)isoxa zole), in the mouse elevated plus-maze test. Results showed that while clozapine (0.3-6.0 mg/kg) dose-dependently inhibited all active behav iours (arm entries, exploration, rearing) and increased grooming and i mmobility, it failed to alter the major anxiety indices (percent open entries and open time). In contrast, L-745,870 (0.02-1.5 mg/kg) and L- 741,742 (0.04-5.0 mg/kg) did not produce any significant behavioural c hanges under present test conditions. These data, which contrast marke dly with the robust anxiolytic profile of the reference compound, chlo rdiazepoxide (10.0 mg/kg), provide little support for the suggestion t hat clozapine possesses anxiolytic-like properties and further indicat e that selective dopamine D, receptor antagonists are ineffective in t he modulation of anxiety-related behaviours in the plus-maze. (C) 1997 Elsevier Science B.V.