Effects of olanzapine, sertindole and clozapine on MK-801 induced visual memory deficits in mice Oguz Mutlu ⁎, Güner Ulak 1 , Ipek Komsuoglu Celikyurt 2 , Füruzan Yıldız Akar 3 , Faruk Erden 4 , Pelin Tanyeri 2 Kocaeli University Medical Faculty, Pharmacology Department, 41380-Kocaeli, Turkey abstract article info Article history: Received 13 March 2011 Received in revised form 3 June 2011 Accepted 8 June 2011 Available online xxxx Keywords: Atypical antipsychotics Cognition Novel object recognition test Open field test MK-801 Mice We investigated the effects of the second generation antipsychotics olanzapine, sertindole and clozapine on visual recognition memory using the novel object recognition (NOR) test in naive and MK-801-treated animals. The effects of drug treatment on locomotion and anxiety were also determined using the open field test. Male Balb-c mice were treated with olanzapine (0.2, 0.4 and 0.6 mg/kg; i.p.), sertindole (0.63, 1.3 and 2.5 mg/kg; s.c.) or clozapine (0.5 and 1 mg/kg; i.p.), and cognitive deficits were induced by MK-801 (0.2 mg/kg; i.p.) administration. Olanzapine treatment decreased the ratio index in the NOR test, whereas sertindole and clozapine had no effect in naive mice. MK-801-induced cognitive impairment was reversed by treatment with olanzapine, sertindole or clozapine. While olanzapine, sertindole and clozapine had no effect on the anxiety of naive mice as determined by the open field test, MK-801 significantly increased the total distance traveled, time spent in the center zone and the velocity of the animals. MK-801-induced effects on locomotion and anxiety in the open field test were reversed by olanzapine, sertindole or clozapine treatment. The results of the present study demonstrated that olanzapine, sertindole and clozapine improved cognition in MK-801 treated mice, and indicate that these drugs have a potential to improve cognition in schizophrenia. © 2011 Elsevier Inc. All rights reserved. 1. Introduction The effects of antipsychotics on cognition are controversial, and classical antipsychotics have been postulated to cause more cognitive deterioration than atypical antipsychotics (Purdon et al., 2001; Gallhofer, 1999). In clinical studies, the second generation atypical antipsychotic agents, like clozapine, ziprasidone, quetiapine and olanzapine, improved cognitive impairment, whereas typical agents, such as haloperidol, had no effect (Harvey and Keefe, 2001; Purdon et al., 2001). In preclinical cognitive tests, varying results on normal cognitive functions have been observed with atypical antipsychotics (Didriksen, 1995; Skarsfeldt, 1996; Didriksen et al., 2006). Clozapine is considered the “prototypical” atypical antipsychotic. It has proven particularly efficacious in instances in which other antipsychotics fail. Although it is very effective, clozapine is not considered a first-line agent because it can lead to potentially life- threatening side effects (Alvir et al., 1993). Olanzapine is a 5HT 2A /D 2 antagonist that possesses a chemical structure similar to that of clozapine. Even at high doses, it induces only mild extrapyramidal side effects, and it is commonly used in the clinic. Olanzapine has M 1 ,H 1 and alpha 1 antagonistic properties, which all cause sedation (Bymaster et al., 1996). Sertindole is a new atypical antipsychotic with 5HT 2A /D 2 antagonism. In previous studies, it has been shown to have a unique pharmacological profile. Sertindole has been proven to have beneficial effects in treatment-resistant patients; however, it also has cardiovas- cular side effects (Arnt and Skarsfeldt, 1998). The effects of sertindole on cognitive function in humans have not been extensively investigated. The N-methyl-D-aspartate (NMDA) receptor is a subclass of ionotropic glutamate receptors. Antagonists of the NMDA receptor block hippocampal long-term potentiation and impair hippocampal- dependent behavior (e.g., spatial memory tasks) (Bischoff and Tiedtke, 1992). Non-competitive antagonists of the NMDA receptor, such as ketamine or phencyclidine (PCP), have strong psychotomi- metic effects in humans (Javitt and Zukin, 1991). MK-801 is a non- competitive antagonist that binds to the PCP binding site within the NMDA receptor-ion complex (Wong and Nielsen, 1989). It impairs animal performance in various learning and memory paradigms (Castellano et al., 2001; Riedel et al., 2003). MK-801 also produces various effects on rodent behavior, including deficits in sensory processing (Al-Amin and Schwarzkopf, 1996), hypermotility (Carls- son, 1993), stereotypy and ataxia (Tricklebank et al., 1989). Pharmacology, Biochemistry and Behavior 99 (2011) 557–565 ⁎ Corresponding author at: Department of Pharmacology, Faculty of Medicine, Kocaeli University, 41380 Kocaeli, Turkey. Tel.: +90 262 303 72 50; fax: +90 262 303 70 03. E-mail addresses: oguzmutlu80@hotmail.com (O. Mutlu), gunerulak@yahoo.com (G. Ulak), ikomsu@hotmail.com (I.K. Celikyurt), firuzanakar@gmail.com (F.Y. Akar), faruk.erden@isbank.net.tr (F. Erden), pelintanyeri@yahoo.com (P. Tanyeri). 1 Tel.: +90 262 303 74 66. 2 Tel.: +90 262 303 74 57. 3 Tel.: +90 262 303 74 64. 4 Tel.: +90 262 303 80 05. 0091-3057/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.pbb.2011.06.011 Contents lists available at ScienceDirect Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh