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


OBJECTIVE
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.


METHODS
Rats learned a conditional discrimination task where reinforcement was contingent on an appropriate lever press during a specific auditory stimulus.


RESULTS
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.


CONCLUSIONS
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.
Dunn
Michael J
MJ
Department of Health and Social Sciences (Psychology), University of Wales Institute Cardiff (UWIC), Llandaff Campus, Western Avenue, Cardiff, CF5 2SG, UK. mdunn@uwic.ac.uk
Killcross
Simon
S
D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects*; D001552:Benzazepines / Q000494:pharmacology* / Q000627:therapeutic use; D003024:Clozapine / Q000494:pharmacology* / Q000627:therapeutic use; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000139:chemically induced / Q000517:prevention & control / Q000523:psychology; D003214:Conditioning, Classical / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects; D018492:Dopamine Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists; D005108:Extinction, Psychological / Q000187:drug effects; D005475:Flupenthixol / Q000494:pharmacology* / Q000627:therapeutic use; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D010622:Phencyclidine; D011237:Predictive Value of Tests; D051381:Rats; D015203:Reproducibility of Results; D012702:Serotonin Antagonists / Q000494:pharmacology* / Q000627:therapeutic use
D014150:Antipsychotic Agents; D001552:Benzazepines; D018492:Dopamine Antagonists; D018691:Excitatory Amino Acid Antagonists; D012702:Serotonin Antagonists; D005475:Flupenthixol; D010622:Phencyclidine; D003024:Clozapine; D006220:Haloperidol