Clozapine, SCH 23390 and α-flupenthixol but not haloperidol attenuate acute phencyclidine-induced disruption of conditional discrimination performance

Abstract

Forebrain dopamine (DA) manipulation has recently been shown to selectively disrupt a conditional discrimination task whose design parameters approximate tasks repeatedly shown to be impaired in schizophrenia. To investigate the reversal potential of the D(1)/D(2) receptor antagonist alpha-flupenthixol, the selective D(1) antagonist SCH 23390, the typical antipsychotic haloperidol and the atypical antipsychotic clozapine on acute phencyclidine (PCP)-induced disruption of a conditional discrimination task dependent on the ability to use task-setting cues that inform goal-directed performance. Rats learned a conditional discrimination task where reinforcement was contingent on an appropriate lever press during a specific auditory stimulus. PCP disrupted task performance at 1.5 mg/kg, attenuated correct lever pressing at 2.5 mg/kg and abolished overall responding at 5 mg/kg (experiment 1). Pavlovian-instrumental transfer task results (experiment 2) showed that 1.5 and 2.5 mg/kg PCP had no disruptive effects on basic sensory, motor or motivational processes; however, such deficits were evident in 5-mg/kg-treated animals. PCP (1.5 mg/kg) disruption of conditional discrimination was attenuated by acute pretreatment with clozapine, SCH 23390 and alpha-flupenthixol; however, pretreatment with haloperidol did not attenuate task disruption. The predictive validity of the conditional discrimination model is enhanced as the selective task disruption by the preeminent psychotomimetic PCP is reversed by clozapine (known to ameliorate cognitive deficits in schizophrenia) and the role of DA D(1) receptors as mediators of tasks that require conditional relationships is discussed.