Dopamine D4 receptor and anxiety: behavioural profiles of clozapine, L-745,870 and L-741,742 in the mouse plus-maze.

The dopamine D4 receptor has been implicated in the therapeutic effects of the atypical antipsychotic, clozapine. As it has been proposed that anxiolytic-like activity may contribute to the efficacy of this agent in ameliorating the negative symptoms of schizophrenia, the current study employed ethological methods to fully characterize the acute behavioural profiles of clozapine and two more selective dopamine D4 receptor antagonists, L-745,870 (3-[{4-(4-chlorophenyl)piperazin-1-yl)]methyl}-1 H-pyrrolo[2,3b]pyridine) and L-741,742 (5-(4-chlorophenyl)-4-methyl-3-(1-(2-phenylethyl)piperidin-4-yl)is oxazole), in the mouse elevated plus-maze test. Results showed that while clozapine (0.3-6.0 mg/kg) dose-dependently inhibited all active behaviours (arm entries, exploration, rearing) and increased grooming and immobility, 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 changes under present test conditions. These data, which contrast markedly with the robust anxiolytic profile of the reference compound, chlordiazepoxide (10.0 mg/kg), provide little support for the suggestion that clozapine possesses anxiolytic-like properties and further indicate that selective dopamine D4 receptor antagonists are ineffective in the modulation of anxiety-related behaviours in the plus-maze.