Cognitive deficits in
schizophrenia are associated with poor functional outcome, and may be further aggravated by treatment with
antipsychotics. In the present study the acute and chronic (3 weeks of treatment) effects of
clozapine,
olanzapine, and
sertindole on performance in the Morris water maze in rats was compared, using pharmacologically and/or clinically relevant dose regimens. An experimental design consisting of three trials/day over 3 days was used. Performance was expressed as the distance and latency to find a submerged platform, as well as the percentage of "non-finders", i.e. percentage of trials where the rat was unable to find the platform within the total trial time of 60 s.
Clozapine (40 mg/kg, p.o.) and
olanzapine (2.5 mg/kg, s.c.) impaired water maze performance when given acutely. However, tolerance developed to the deficit induced by
clozapine, whereas the
olanzapine-mediated impairment was enhanced after chronic treatment.
Sertindole (2.5 mg/kg, p.o.) had no disruptive effect on performance after either acute or chronic treatment. Exposure measurements confirmed that all three compounds were present in the serum at least at clinically effective concentrations. Thus, the three
antipsychotics tested differentially affected rodent cognition, whereby
sertindole appeared to have a lower potential than either
clozapine or
olanzapine to induce
cognitive impairment. The hypothesis that the low potency of
sertindole in inducing
dopamine D2 receptor blockade, combined with lack of
antimuscarinic and
histamine H1 antagonist activity in vivo is discussed. Clearly further studies are needed to assess the potential cognition-enhancing effects of
sertindole vs. other
antipsychotics in a relevant animal model of
schizophrenia.