THE EFFECT OF COMBINATION OF RITANSERIN AND HALOPERIDOL ON MK-801-INDUCED BEHAVIOR

1. INTRODUCTION OBJECTIVE OF THE STUDY 5 2.5 5 2.5 control METHODS ritanserin ritanserin Haloperidol MK-801 RESULTS MK-801/RIT 2.5 mk/kg MK-801/RIT 2.5 mk/kg MK-801 MK-801/HAL/RIT 2.5 mk/kg MK-801/HAL/RIT 2.5 mk/kg CONTROL A B REFERENCES 5 2.5 2.5 5 control Bubeníková V et al., 2005 The effect of zotepine, risperidone, clozapine and olanzapine on MK-801-disrupted sensorimotor gating. Pharm Biochem Behav 80:591-596. ritanserin ritanserin Haloperidol MK-801 Bubeníková V., Páleníček T.,Horáček J. Prague Psychiatric Center and Centre of Neuropsychiatric studies, Czech Republic CONCLUSIONS Our results indicate that combination of 5-HT2A/2C receptor antagonism and D2 receptor antagonism has a similar efficacy as ritanserin itself in higher dose (5 mg/kg) to restore the deficit in senzorimotor gating in animal model of schizophrenia like behavior. However, ritanserin itself is more effective then combination of ritanserin with haloperidol to decrease MK-801 induced hyperlocomotion. THE EFFECT OF COMBINATION OF RITANSERIN AND HALOPERIDOL ON MK-801-INDUCED BEHAVIOR A B Serotonin receptors have been suggested to play a critical role in the action of the atypical antipsychotics. Specifically, it has been postulated that antagonism of serotonin 5-HT2A receptors together with dopamine D2 receptor antagonism is the most important feature for the action of atypical antipsychotics. In our experimental design, we induced schizophreni-like behavior by administration of dizocilpine. The aim of the study was to evaluate the effect of 5-HT2A/2C receptor antagonist (ritanserin) itself or in combination with haloperidol (dopamine D2 antagonist) on deficit in prepulse inhibition of startle response (PPI) and hyperlocomotion induced by MK-801 administration. Figure 1. The effect of combination of ritanserin and haloperidol on MK-801 induced deficit in PPI (part B). Spontaneous PPI after adiministration of ritanserin and haloperidol (part A). * p<0.05; *** p<0.001 compare to controls Male Wistar rats were treated by MK-801 (0.3 mg/kg i.p.) and by ritanserin (2.5 and 5 mg/kg s.c.) and by haloperidol (0.1 mg/kg s.c.). The MK-801 and ritanserin were administrated simultaneously 15 minutes before the experiment. Haloperidol was administreted 60 min before. Control rats received the corresponding vehicle. The schedule for PPI (SR-LAB, San Diego Instruments) was described in Bubenikova et al.,2005.Locomotor activity was registreted for 90 min following drug treatments in the arena (68x68x30 cm) by automatic tracking systém (Noldus, EthoVision Color-Pro version 3.0.13). Figure 1. There are no effect of ritanserin or haloperidol on sponataneous PPI (Part A). Part BMeans of groups are significantly different (one-way ANOVA F6,69=3.7; p<0.01). Administration of MK-801 decreased PPI (* p< 0.05). Ritanserine in low dose and haloperidol did not restore the deficit in PPI (* p<0.05; *** p<0.001)induced by MK-801. The value of PPI after combination treatment with ritanserin and haloperidol was similar to control group, however we did not find any effect compare to MK-801 group. As a Pos-hoc test Newman-Keuls multiple comparison test was used. Figure 2. Examples of trajectories after administration of ritanserin, MK-801 and/or haloperidol. Figure 3. Part AMeans of groups are significantly different (one-way ANOVA F3,39=13.8; p<0.001). Administration of haloperidol decreased spontaneous locomotor activity (** p<0.01). Part B Means of groups are significantly different (one-way ANOVA F6,74=14.7; p<0.001). Application of MK-801 increased locomotor activity (***p<0.001). Ritanserin at both doses and haloperidol decreased hyperlocomotion induced by MK-801 (### p<0.001). Combination of ritanserin with haloperidol had similar effect on locomotor activity as haloperidol itself in rats treated with MK-801. As a Pos-hoc test Newman-Keuls multiple comparison test was used Figure 2. The effect of serotonin 5-HT2A/2C antagonist (ritanserin) itself (Part A) or with combination with haloperidol on MK-801 induced hyperlocomotion (Part B). *** p< 0.001 compare to control; ### p<0.001 compare to MK-801 group. This work was supported by the grants MEYS 1M0002375201 and MHCR NL 7684/3 bubenikova@pcp.lf3.cuni.cz www.pcp.lf3.cuni.cz