Reversal of PCP-induced learning and memory deficits in the Morris' water maze by sertindole and other antipsychotics.

Rationale: In humans, the N-methyl-D-aspartate antagonist phencyclidine (PCP) induces behavioral changes that mimic schizophrenia symptoms, including positive and negative symptoms as well as cognitive deficits. In clinic, the cognitive deficits are closely associated with functional outcome. Thus, improvement of cognition may have high impact on patients' daily life.

Objective: In the present study, three second-generation antipsychotics (sertindole, risperidone, and clozapine) as well as the classical antipsychotic haloperidol were tested for the ability to reverse PCP-induced cognitive deficits in the Morris' water maze.

Results: The second-generation antipsychotics reversed the PCP-induced cognitive impairment: sertindole (0.63-2.5 mg/kg, s.c.), risperidone (0.04 mg/kg, s.c.; whereas 0.08 and 0.16 mg/kg were without significant effect), and clozapine (0.63 mg/kg, s.c.; while 1.3 mg/kg was without significant effect). The significant effect of sertindole was observed from day 2 onwards, while clozapine and risperidone only had significant effect at day 3. The classical antipsychotic haloperidol (0.010-0.020 mg/kg, s.c.) was ineffective. No compounds influenced swimming speed at the doses used, indicating that motor function was preserved.

Conclusion: These results confirm that repeated PCP administration induces marked cognitive deficits. Further, second-generation antipsychotics like sertindole, clozapine, and risperidone within a certain, often narrow, dose range are able to reverse the impairment and thus might improve cognitive deficits in schizophrenic patients, whereas classical compounds like haloperidol lack this effect. The receptor mechanisms involved in the reversal of PCP's disruptive effect are discussed and likely include a delicate balance between effects on dopamine D(2), 5-HT(2A/6), alpha-adrenergic, muscarinic, and histaminergic H(1) receptors.