Clozapine but not haloperidol treatment reverses sub-chronic phencyclidine-induced disruption of conditional discrimination performance

Abstract

Abusers of phencyclidine (PCP) often present with a symptom profile similar to that exhibited by schizophrenic patients. Animal models utilising such psychotomimetics are currently informing research into the condition. Accumulating evidence suggests that a central cognitive deficit in schizophrenia is the inability to use task-setting cues to guide goal directed behaviour and that this ability is mediated by prefrontal dopamine (DA). The current study used the non-competitive NMDA antagonist phencyclidine (PCP) and Haloperidol (typical antipsychotic) and Clozapine (atypical antipsychotic) in order to further investigate the influence of DAergic manipulation on a task that requires the use of conditional information to inform goal-directed performance. An instrumental conditional discrimination task was employed in which rats learn to respond appropriately according to the presence of specific auditory conditional stimuli. Probe test 1 showed impaired conditional discrimination performance following sub-chronic PCP administration (seven twice-daily injection protocol) compared to control which was reversed by acute treatment with clozapine (5 mg/kg) but not haloperidol (0.1 mg/kg) both administered 60 min pre-test. Probe test 2 (8 days post-treatment) showed enduring deficits to conditional discrimination performance that were again reversed by clozapine but not haloperidol (injection procedures as above). These results show that tasks dependent upon conditional relationships are particularly sensitive to manipulation of DAergic systems as prolonged treatment with PCP has been shown to selectively reduce prefrontal cortex (PFC) DA activity and treatment with clozapine (known to ameliorate cognitive deficits) but not haloperidol has been shown to selectively restore PFC DA levels.