Effects of haloperidol on MK-801-induced memory deterioration in the Morris water maze and radial-arm maze tests in mice

O Mutlu, G Ulak, I Celikyurt, F Akar, T Demirtas, E Bektas, F Erden. Kocaeli University Medical Faculty, Pharmacology/41380, Turkey

Cognitive dysfunction is frequently seen in many schizophrenic patients and may be further aggravated by antipsychotic treatments. While atypical antipsychotics have some beneficial effects on the cognitive dysfunction in schizophrenia, typical antipsychotics lack the ability to improve cognitive dysfunction in schizophrenics (Harvey and Keefe, 2001). In humans, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists induce schizophrenia-like symptoms including cognitive symptoms (Krystal et al., 1994). Therefore, NMDA receptor antagonist-treated animals have been used as models for schizophrenia. A highly specific non-competitive NMDA receptor antagonist MK-801(dizocilpine) impairs learning and memory functions that depend on the hippocampus and the amygdala (Jafari-Sabet, 2006). Haloperidol is a classical antipsychotic drug used in schizophrenia and psychosis.

The aim of this study was to investigate the effects of haloperidol on spatial memory in mice, using the Morris water maze (mwm) and radial arm maze (ram) tests, common and well-known tests to evaluate learning and memory functions ; moreover the effects of haloperidol on MK-801 induced cognitive dysfunction was also evaluated. 30-40 g male balb-c mice were treated with haloperidol (0.05, 0.075 mg/kg) or MK-801 alone or concurrently (n=6). Haloperidol and MK-801 were administered intraperitoneally 60 min. and 30 min. before the daily performance of mwm test subchronically for 6 days and acutely before the retention trial of ram test. One way Anova post hoc Tukey’s test was used as statistical analysis method. The results of this study revealed that (1) In the mwm test, MK-801 significantly increased escape latency starting from the 2nd acquisition session (178±2) compared to control group (97.16±5.27) (p<0.001) and haloperidol failed to reverse this effect (MK+hal0.05=160.5±16.27; MK+hal0.075=176±4). Time spent in escape platform’s quadrant in the probe trial significantly decreased in MK-801 (9.5±1.23), haloperidol (hal0.05=12.54±3.05; hal0.075=18.09±1.87), and haloperidol+MK-801 treated animals (MK+hal0.05=9±2.85; MK+hal0.075=4.95±2.33) (p<0.001) compared to control group (34.68±1.80). Mean distance to platform in the probe trial significantly increased in MK-801 (31.57±1.47) (p<0.01), haloperidol 0.05 (32.62±2.60) (p<0.01) and haloperidol+MK-801 treated animals (MK+hal0.05=34.76±2.25; MK+hal0.075=42.04±2.88) (p<0.001) compared to control group (20.28±1.69). There was no significant difference between the speed of the animals in the mwm test (p>0.05) (control=18.29±2.26; hal 0.05=20.16±2.41; hal 0.075=17.38±1.48; MK=14.93±1.45; MK+hal0.05=16.35±2.94; MK+hal0.075=13.86±1.60). (2) In the ram test, MK-801 significantly increased the number of errors in the retention trial (11±0.57) (p<0.001) compared to control group (1±0.44) and haloperidol failed to reverse this effect (MK+hal0.05=6.83±1.53; MK+hal0.075=9.66±1.22). There was no significant difference between the retention latency of the animals (p>0.05) (control=5.77±0.41; hal 0.05=9.43±1.46; hal 0.075=8.05±1.98; MK=3.85±0.16; MK+hal0.05=8.98±1.99; MK+hal0.075=5.41±1.63). The speed of the animals significantly increased in MK-801 group (9.24± 0.40) (p<0.001) compared to control group (3.98±0.37) and concurrent administration of haloperidol (doses used) and MK-801 reversed MK-801 induced enhancement on speed (p<0.05) (MK+hal0.05=4.83±0.94; MK+hal0.075=5.73±1.12). Our results revealed that MK-801 exerted spatial memory impairment in mwm and ram tests; moreover haloperidol failed to improve MK-801 induced memory deterioration in mice.

Harvey PD, Keefe RS (2001) Am J Psychiatry 158: 176–184

Jafari-Sabet M (2006) Eur J Pharmacol 529: 122–128

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