TY - JOUR
T1 - Sertindole, in contrast to clozapine and olanzapine, does not disrupt water maze performance after acute or chronic treatment
AU - Didriksen, Michael
AU - Kreilgaard, Mads
AU - Arnt, Jørn
PY - 2006/8/7
Y1 - 2006/8/7
N2 - 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.
AB - 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.
KW - Analysis of Variance
KW - Animals
KW - Antipsychotic Agents
KW - Behavior, Animal
KW - Benzodiazepines
KW - Clozapine
KW - Dose-Response Relationship, Drug
KW - Imidazoles
KW - Indoles
KW - Male
KW - Maze Learning
KW - Psychomotor Performance
KW - Rats
KW - Rats, Wistar
KW - Time Factors
U2 - 10.1016/j.ejphar.2006.05.021
DO - 10.1016/j.ejphar.2006.05.021
M3 - Journal article
C2 - 16806167
SN - 0014-2999
VL - 542
SP - 108
EP - 115
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 1-3
ER -