RATIONALE:

Recent experimental findings suggest that a core cognitive deficit of schizophrenia is the degraded ability to use task-setting cues to guide goal-directed behaviour, that this deficit is evident in acute as well as chronic schizophrenia, and that such deficits can me modelled in animals using conditional discrimination tasks.

OBJECTIVE:

To establish the reversal potential of D1, D2 and 5-HT receptor antagonists acutely, and D1 and D2 receptor antagonists chronically, on d-amphetamine-induced disruption of a conditional discrimination task that depends on the ability to use task-setting cues to direct goal directed performance.

METHOD:

A conditional discrimination paradigm was employed in which rats learned to respond on an appropriate lever, conditional upon specific auditory stimuli.

RESULTS:

d-Amphetamine (1.5 mg/kg) disruption of conditional discrimination was attenuated by acute pre-treatment with the selective D1 antagonist SCH 23390 and the atypical anti-psychotic clozapine (Cloz). Acute pre-treatment with the selective D2 antagonist eticlopride (Eti) and the anti-psychotic haloperidol (Hal) failed to reverse d-amphetamine disruption, as did pre-treatment with the selective 5HT1A antagonist WAY 100635 and the selective 5HT2A/C antagonist ritanserin. However, Eti and Hal did reverse d-amphetamine-induced task disruption when administered chronically (as did SCH 23390, alpha-flupenthixol and Cloz).

CONCLUSIONS:

These results suggest that D1 receptors are involved in tasks that require the use of conditional relationships and that D2 receptor antagonism can come to exert a similar influence after chronic treatment.