Analysis of sensitivity to MK-801 treatment in a novel active allothetic place avoidance task and in the working memory version of the Morris water maze reveals differences between Long-Evans and Wistar rats

Analysis of sensitivity to MK-801 treatment in a novel active allothetic place avoidance task and in the working memory version of the Morris water maze reveals differences between Long-Evans and Wistar rats
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  Analysis of sensitivity to MK-801 treatment in a novel active allotheticplace avoidance task and in the working memory version of the Morriswater maze reveals differences between Long-Evans and Wistar rats Karel Vales a , Vera Bubenikova-Valesova b , Daniel Klement a , Ales Stuchlik  a, * a  Institute of Physiology, Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic b Prague Psychiatric Center, Ustavni 91, 18103 Prague, Czech Republic Received 13 February 2006; accepted 7 April 2006Available online 19 May 2006 Abstract The aims of the present study were to compare the effect of subchronic administration of MK-801 on performance in the active allothetic placeavoidance (AAPA) task and in the working version of Morris water maze (MWM) in Long-Evans and Wistar rats. Animals were trained for fourdaily sessions either in the AAPA or in the working memory version of the MWM. Wistar rats treated by MK-801 (0.1 mg/kg) showed a cognitivedeficit in the AAPA task without a significant hyperlocomotion, whereas they were not impaired in the working memory version of the MWMcompared to controls. Long-Evans rats treated by MK-801 (0.1 mg/kg) were not impaired either in the AAPA task or in the MWM task. Higherdoses of MK-801 (0.2 and 0.3 mg/kg) produced hyperlocomotion in both strains which corresponded to an inability to solve both spatial tasks.Long-Evans rats were superior in the MWM to the Wistar rats in the groups treated with the low dose of MK-801. In conclusion, intact Wistar ratscanefficientlysolvebothspatialtasks;however,theyaremoresensitivetoMK-801-inducedbehaviouraldeficit.Thishasrelevanceformodelingof the schizophrenia-related deficits and for screening substances for their therapeutic potential. # 2006 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved. Keywords:  Animal model of schizophrenia; MK-801; Strain differences; Spatial cognition; Active allothetic place avoidance; Working memory; Morris watermaze 1. Introduction Spatial navigation ranks among the most prominent andmost intensively studied types of behaviour in various animalspecies, including laboratory rodents. Rodent navigation todirectlyimperceptiblegoals(placenavigation)hasbeenstudiedin detail in the past 50 years, and is today considered by someauthors as an animal model of higher cognitive functions inhumans (for review see Gallistel, 1990; O’Keefe and Nadel,1978).Place navigation can be in principle implemented by twomodes—allothetic (O’Keefe and Nadel, 1978) and idiothetic(Mittelstaedt and Mittelstaedt, 1980; Etienne and Jeffery,2004). During the allothetic navigation the subject computes itsposition with respect to environmental stimuli, spatial cues orlandmarks. The second mode of place navigation, idiotheticnavigation, is based on continuous integration of self-motionsignals, e.g. angular and radial accelerations, proprioception,haptic and optic flow and presumably efference copies of motorcommands.Standard spatial tasks designed for rodents study spatialbehaviour in stable environments. A typical experimentalparadigm in place navigation research is the Morris water mazein which rats search for a submerged platform in a circular poolfilled with water (MWM; Morris, 1984). Two modifications of this task are used—reference memory and working memoryversions. Inthe referencememoryversionof MWM, the escapeplatform position remains stable across daily sessions, whilst itis changed daily in the working memory version of the MWM(Morris, 1984; for a recent review see Dudchenko, 2004). In the working memory version, animals’ ability to find the platformon the second trial is at the asymptotic level on the fourthdaily session (Steele and Morris, 1999). Prominent mode of navigation in the MWM is allothesis, although idiothesis was Research 55 (2006) 383–388* Corresponding author. Tel.: +420 241 062 538; fax: +420 241 062 488. E-mail address: (A. Stuchlik).0168-0102/$ – see front matter # 2006 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.doi:10.1016/j.neures.2006.04.007  demonstrated to play a limited role (Moghaddam and Bures,1996; Benhamou, 1997).Recently, another behavioural paradigm called placeavoidance was introduced by our laboratory (Bures et al.,1997; Cimadevilla et al., 2000). In this task, rats avoid anunmarked region on an arena using proximal cues bound to thearena surface, e.g. feces, urine, scent marks; (arena referenceframe) and simultaneously using distal cues bound to the room(room reference frame; Fenton et al., 1998). The arena and theroom coordinate frames overlap on the stable arena. In arecently designed modification of the place avoidance task, theactive allothetic place avoidance (AAPA), rats are trained toactively avoid a room frame-defined sector on a continuouslyrotating arena (Cimadevilla et al., 2000, 2001). The rotation of the arena continuously physically dissociates the room framefrom the arena frame. Animals are thus required to solve aconflict between two subsets of spatial stimuli: the room frameinformationontheonehandandthearenaframeinformationonthe other hand, and toselect the room frame as the only relevantfor efficient navigation. It must be pointed out that besidecognitive coordination (Wesierska et al., 2005), allothesis isalso necessary for efficient AAPA performance, although itsaccuracy demand is probably lower in the AAPA than in theMWM (considerasmallplatforminthe MWMcomparedtothe1/6 of arena in the AAPA; Stuchlik et al., 2004; Vales andStuchlik, 2005).The neurodevelopmental hypothesis of schizophrenia pre-sumes that abnormalities in the brain glutamatergic circuits playaroleinpathogenesisofthisdiseaseandareinvolvedincognitivedeficit observed in patients with schizophrenia (Konradi andHeckers,2003;Riedeletal.,2003).Glutamatergic-hypofunctionmodel of schizophrenia-like behaviour (having high face andpredictivevalidities)wasrecentlydesigned(Nilssonetal.,2001).In this model, experimental psychosis is induced by a systemicadministrationofdizocilpine(MK-801).ApplicationofMK-801increases locomotor activity, impairs sensorimotor gating andcauses other alterations of neural functions, which can bereversedbyantipsychotics (Swerdlow etal.,1998;Andine etal.,1999; Bubenı´kova´ et al., 2005).We selected the AAPA task for testing the putative cognitivedeficit in MK-801-treated rats, because this task requires thatthe animals separate spatial stimuli from the environment intocoherent representations (Wesierska et al., 2005), and deficit inthis ability could be analogous to the inability of schizophrenicpatients to distinguish between relevant and irrelevantinformation (Ellenbroek and Cools, 1990). Such cognitivedisorganization symptom of schizophrenia was describedelsewhere (Phillips and Silverstein, 2003).Recently we have published that MK-801-treated Long-Evans rats are unable to avoid the punished sector in the AAPAtask and their reference memory in the MWM is impaired(Stuchlik et al., 2004; Stuchlik and Vales, 2005), whichsupports the face validity of this particular model. Since it wasdemonstrated that working memory is selectively impaired inpatients suffering from schizophrenia (Meltzer et al., 1999;Glahn et al., 2003), we also focused on the working memoryversion of the MWM in MK-801-treated rats.The aim of the present study was to compare the effect of MK-801 on performance in AAPA task and in working versionof MWM task in adult male pigmented rats of the Long-Evansstrain and in albino rats of the Wistar strain. Both albinos andpigmented rats are used in experiments modeling schizo-phrenia-like behaviour. Albino (Wistar or Sprague–Dawley)rats are often used for pharmacological research, whilstpigmented rats have been shown better performance in severalcognitive tasks (Andrews et al., 1995). Elucidation of straindifferences in cognitive deficits induced by MK-801 could berelevant in efforts of the search for novel drugs with possibleuse in schizophrenia. 2. Materials and methods 2.1. Animals All manipulations were done in accord with the Law on Animal Protectionof Czech Republic and with the appropriate directive of the European Union(86/609/EEC). Sixty naive male adult rats of the Long-Evans strain (5-month-old, weighing 350–450 g) and 60 male adult rats of the Wistar strain (5-month-old, weighing 350–450 g) obtained from the Institute’s breeding colony (Long-Evans rats) and from SPF breeding colony in Konarovice, Czech Republic(Wistar rats) were used in the experiments. Animals were accommodated in25 cm  30 cm  45 cm transparent plastic cages per two in a laboratory air-conditioned animal room with constant temperature (22  8 C) and 12:12 light/ dark cycle (with the lights on at 7:00 a.m.). Water and food were available adlibitum throughout the experiments.Animals selected for the training in the AAPA were implanted under lightdiethyl ether anesthesia with a low-impedance subcutaneous connector madefrom a thin surgical needle, which pierced the rat’s skin between the shoulders.The sharp end of the needle was cut off and bent with tweezers to form a smallloop, which prevented the connector from slipping out and provided anchor foran alligator clip, which was connected to a shock-delivering wire. 2.2. Drug treatment  MK-801 (dizocilpine maleate; [5  R ,10 S  ]-[+]-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine; Sigma–Aldrich, Czech Republic) wasdissolved in saline (0.1, 0.2 and 0.3 mg/ml) and injected intraperitoneally30 min before each training session (0.1, 0.2 and 0.3 mg/kg b.w.). Animalsfromthecontrolgroupwereinjectedwithsaline(1 ml/kgb.w.).Allanimalsthusreceived injections of the same volume of liquid per kg of weight. 2.3. Apparatuses and behavioural procedures TheAAPAapparatuswasdescribedindetailinourpreviouspaper(seeFigs.1 and 3 of  Stuchlik and Vales, 2005). Briefly, it consisted of a smooth metalliccircular arena (80 cm in diameter) enclosed with a 30 cm high transparentPlexiglas wall and elevated 1 m above the floor of the dimly lighted 4 m  5 mroom with abundance of extramaze landmarks. At the beginning of eachtraining session, a rat was placed on the rotating arena (1 rpm) opposite to adirectly imperceptible 60 8  shock sector, defined in the north of the cardinalcompass direction (N, S, W, E) by the custom-based computer tracking system,located in an adjacent room. The location of the shock sector could bedetermined solely by its spatial relations to distal orienting cues located intheroom.Theratworeaninfraredlight-emittingdiode(LED),fixedbetweenitsshoulders with a light latex harness, and its position was tracked every 40 msand recorded onto a computer track file, allowing subsequent reconstruction of the track with an off-line custom-based analysis program. Whenever the ratentered the shock sector for more than 0.5 s, mild electric shocks (50 Hz, 0.5 s)were delivered at intervals of 1.5 s until the rat left the shock sector for at least0.5 s. The shocks were delivered through a thin subcutaneous low-impedanceconnector implanted on the back of the rat standing on the grounded floor. K. Vales et al./Neuroscience Research 55 (2006) 383–388 384  The appropriate shock current (ranging between 0.4 and 0.7 mA) was indivi-dualized for each rat to elicit a rapid escape reaction but not freezing.Experimental sessions in AAPA lasted 20 min and each rat had one sessionevery day, carried out during daylight hours for four days. Arena surface wasthoroughly cleaned after each rat, so a particular animal could only use self-generated local cues.The MWM apparatus was a blue-painted circular metallic pool (187 cm indiameter, 40 cm high) filled with water (20  8 C). Rats were released from fourcardinal compass points (marked as S, N, W, E) chosen pseudorandomly at theperiphery of the pool and they were allowed to swim until they found atransparent circular platform (10 cm in diameter; submerged 1 cm below thewatersurface)oruntil60 selapsed.Ratsweretrainedfor4days.Thepositionof the platform was varying pseudorandomly from day to day. Each day consistedof eight trials with pseudorandom starting location with an inter-trial interval of 60 s. The escape latency in each trial was recorded. However, we were not ableto measure the locomotor activity during the MWM task. 2.4. Design of experiments and data analysis Long-Evansrats(  N   = 60)wererandomlydividedintotwogroups.Theratsinthefirstgroup,consistingof32animals,weretrainedintheAAPAtask;thesecondgroup,consistingof28animals,wastrainedintheworkingmemoryversionoftheMWM task. Each group was further divided into four subgroups ( n  = 8 for theAAPA experiment and  n  = 7 for the MWM experiment). The subgroups differedinthedrugthatratsreceived30 minpriortoeachsession(saline,0.1,0.2,0.3 mg/ kg of MK-801). Wistar rats (  N   = 60) were divided in the same way.The following parameters were recorded during each day and analyzed inorder to assess behaviour of rats in the AAPA. The total distance traveled in asession (total distance) measured in the arena frame (which only takes intoaccount the active locomotion) reflected the locomotor activity of rats. Thenumber of entrances into the shock sector (errors) reflected the efficiency of spatialperformanceintheAAPAtask.Themaximumtimearatspentinthesafepart of the arena between two errors in a particular session was also recorded(maximum time avoided). It reflected the ability to remember the shock sectorlocation and to avoid it.In the MWM task, the escape latencies for second trial were extracted fromthe off-line analysis and used as a measure of the spatial learning efficiency,since performance in further trials (third etc.) can be also influenced byreference memory (Dudchenko, 2004). 2.5. Data analysis and statistics Data from the 4th day of training in AAPA task (asymptotic level of controlanimals; Stuchlik et al., 2004) were analyzed by two-way ANOVAwith factorsstrain and drug. Where significance was attained, post-hoc Bonferroni’s multi-ple comparison test (GraphPad Prism, Version 4; USA). The effect of MK-801within one strain was performed by one-way ANOVA with subsequent com-parisontocontrolsbymeansofDunnett’stest.Thesignificancewasacceptedonthe probability level of 5%.The second trials for each day separately were analyzed in the MWM bytwo-way ANOVAwith post-hoc Bonferroni’s multiple comparison test (Graph-Pad Prism, Version 4; USA) on asymptotic level of control animals (4th day of experiment; Steele and Morris, 1999). The significance was accepted on theprobability level of 5%. 3. Results Visual inspection of rats revealed no increased defecation orother signs of behavioural discomfort during and afterinjections. Rats treated with 0.1 mg/kg of MK-801 and controlrats had intact main reflexes, such as depth avoidance, graspingreflex, and tilted-platform test. In rats treated with the moderateand highest dose of MK-801 (0.2 and 0.3 mg/kg) we visuallyobserved hyperactivity, which was confirmed by measuringtotal distance (see below). Animals treated with the highestdose of MK-801 (0.3 mg/kg) were impaired in their posturalreflexes;theysometimesfell, especiallyafter rearing. However,control rats and rats treated with 0.1 and 0.2 mg/kg respondedto footshocks with immediate escape reactions (and sometimeswith mild vocalizations), suggesting that, although their painperceptioncouldbealteredbyMK-801, theshock intensitywashigh enough to induce avoidance behaviour. 3.1. Testing in the active allothetic place avoidance task  Total distance traveled in a session was not changing inrespective groups during training. During the four sessions wedid not observe any sensitization or tolerance of locomotion toMK-801 treatment. In addition, there was no habituation of locomotor activity in controls. Two-way ANOVA showed theeffect of drug [ F  (3,63) = 24.7;  p < 0.001], but not the effect of strain [ F  (1,63) = 2.35; NS] and no interaction [ F  (3,63) = 2.2;NS](Fig.1).Theeffectofdrugontotaldistancewasassessedinboth strains by one-way ANOVAs. Wistar rats as well as Long-Evans rats increased locomotor activity [Wistar:  F  (3,31) = 8.9;  p < 0.001, Long-Evans:  F  (3,31) = 20.26;  p < 0.001]. Dun-nett’s post-hoc test showed in both strains dose-dependentincrease in total distance (Wistar: control < 0.2 mg/kg MK-801,  p < 0.01, control < 0.3 mg/kg MK-801,  p < 0.01; Long-Evans: control < 0.2 mg/kg MK-801,  p < 0.01, control < 0.3 mg/kg MK-801,  p < 0.01).As concerns errors, a two-way ANOVA showed the effect of strain [ F  (1,63) = 13.41;  p < 0.001] and drug [ F  (3,63) = 46.28;  p < 0.001],butnointeraction[ F  (3,63) = 1.94;NS](Fig.2).TheBonferroni’s multiple comparison post-hoc test showed differ-ence between strains on the low dose of MK-801 (0.1 mg/kg)whereWistarratshadhighernumbersoferrorsthenLong-Evansrats(  p < 0.01).Theeffectofdrugonerrorswasassessedinbothstrains by one-way ANOVAs. Wistar rats as well as Long-Evansrats increased number of errors after 0.2 and 0.3 mg/kg of MK-801 [Wistar:  F  (3,31) = 16.8;  p < 0.001, Long-Evans:  F  (3,31)= 35.9;  p < 0.001]. Dunnett’s post-hoc test showed in bothstrains dose-dependent increase in number of errors (Wistar:control < 0.2 mg/kg MK-801,  p < 0.01, control < 0.3 mg/kgMK-801,  p < 0.01; Long-Evans: control < 0.2 mg/kg MK-801,  p < 0.01, control < 0.3 mg/kg MK-801,  p < 0.01; Fig. 2). K. Vales et al./Neuroscience Research 55 (2006) 383–388  385Fig. 1. The effect of MK-801 on total distance on the fourth session. Valuesrepresent mean (  S.E.M.). Two-way ANOVA (strain and MK-801 treatment asfactors) showed only the effect of drug [ F  (3,63) = 24.7;  p < 0.001]. The effectof drug on total distance showed [one-way ANOVA; Wistar:  F  (3,31) = 8.9;  p < 0.001, Long-Evans:  F  (3,31) = 20.26;  p < 0.001] dose-dependent increaseintotaldistanceinbothstrains(Dunnett’spost-hoctest##  p < 0.01comparedtocongruent controls).  As concerns maximum time avoided, we found thedifferences between strains in this parameter. The two-wayANOVA showed the effects of drug [ F  (3,63) = 33.5;  p < 0.001], strains [ F  (1,63) = 17.04;  p < 0.001] and interac-tion [ F  (3,63) = 10.2;  p < 0.001]. The Bonferroni’s multiplecomparison post-hoc showed difference between the strainsonly after administration of the low dose (0.1 mg/kg) of MK-801 (  p < 0.001). The effect of drug on maximum timeavoidance assessed by one-way ANOVAs was significant inboth strains [Wistar:  F  (3,31) = 13.64;  p < 0.001; Long-Evans: F  (3,31) = 27.55;  p < 0.001]. Dunnett’s post-hoc test in Wistarrats showed that all doses of MK-801 decreased maximum timeavoidance (control < 0.1 mg/kg MK-801,  p < 0.01, control < 0.2 mg/kgMK-801,  p < 0.01,control < 0.3 mg/kgMK-801,  p < 0.01). In Long-Evans rats the drug decreased theperformance from the moderate dose of MK-801 (control < 0.2 mg/kgMK-801,  p < 0.01,control < 0.3 mg/kgMK-801,  p < 0.01; Fig. 3). 3.2. Testing in the Morris water maze task  The escape latencies for second trial after administration of 0.2 and 0.3 mg/kg of MK-801 were 60 s. Animals treated withthese doses were never able to find the platform by themselves,theyalways hadtobeled toit by anexperimenter.Thereforeweevaluated only latencies after administration of low dose of MK-801 (0.1 mg/kg). Two-way ANOVA showed the effect of strain [ F  (1,27) = 16.26;  p < 0.001], but not the effect of drug[ F  (1,27) = 0.14; NS], and no interaction [ F  (1,27) = 0.85; NS].The Bonferroni’s multiple comparison post-hoc test showeddifference between strains after the low dose of MK-801(0.1 mg/kg), where Wistar rats had higher latency compared toLong-Evans rats;  p < 0.01 (Fig. 4). 4. Discussion Results of the present study demonstrate that MK-801 dose-dependently increased locomotor activity in rats of both strains.Theeffectofnon-competitiveNMDAreceptorantagonistssuchas MK-801 onlocomotor activityis currently being studied intogreat depth (Martin et al., 1997; Andine et al., 1999;Bubenı´kova´ et al., 2004). It is believed that MK-801 inducedhyperlocomotion represents an example of schizophrenia-likebehaviour in animals and corresponds to positive symptoms inschizophrenia (Andine et al., 1999). We did not find anydifferences between strains either in spontaneous locomotoractivity or after administration of MK-801.In this study we were mainly interested in cognitivefunctions related to schizophrenia-like behaviour. The aim of the study was to validate MK-801 induced deficit in cognitivefunction in two different strains of rats. The inability toorganize information into coherent subsets in the AAPA task presents the deficit in information processing and attention andit can be a marker of overall cognitive disorganization(Cimadevilla et al., 2001; Stuchlik et al., 2004; Stuchlik and K. Vales et al./Neuroscience Research 55 (2006) 383–388 386Fig. 2. The effect of MK-801on the numberof errors in bothstrains on 4th day.Values represent mean (  S.E.M.). Two-way ANOVA showed the effect of strain [ F  (1,63) = 13.41;  p < 0.001] and drug [ F  (3,63) = 46.28;  p < 0.001]. TheBonferroni’s multiple comparison post-hoc test showed that the number of errors was higher in Wistar rats compared to Long-Evans rats after adminis-tration of MK-801 (0.1 mg/kg);  **  p < 0.01. Both strains increased the numberof errors [one-way ANOVA; Wistar:  F  (3,31) = 16.8;  p < 0.001, Long-Evans: F  (3,31) = 35.9;  p < 0.001]. Dunnett’s post-hoc test showed that administrationof higher doses of MK-801 increased the number of errors compared tocongruent control;  ##  p < 0.01.Fig. 3. The effect of MK-801 on the maximum time avoided in both strains on4th day. Values represent mean (  S.E.M.). The two-way ANOVA showed theeffects of drug [ F  (3,63) = 33.5;  p < 0.001], strains [ F  (1,63) = 17.04;  p < 0.001]andinteraction[ F  (3,63) = 10.2;  p < 0.001].TheBonferroni’smulti-ple comparison post-hoc showed a decrease of the maximum time avoided inWistar rats after the administration of 0.1 mg/kg of MK-801 ( ***  p < 0.001), butnot in Long-Evans rats. Higher doses of MK-801 decreased the parameter inboth strains [one-way ANOVA; Wistar:  F  (3,31) = 13.64;  p < 0.001; Long-Evans:  F  (3,31) = 27.55;  p < 0.001]. Dunnett’s post-hoc test showed the statis-tical difference compared to congruent controls,  ##  p < 0.01.Fig. 4. The effect of MK-801 (0.1 mg/kg) on performance in working memoryversion of the Morris water maze in Wistar and Long-Evans rats. Valuesrepresent mean of escape latencies from second trial (+S.E.M.) on 4th day.Two-way ANOVA showed statistically significant only the effect of strain[ F  (1,27) = 16.26;  p < 0.001]. The Bonferroni’s multiple comparison post-hoctest showed the lower latency in Long-Evans rats compared to Wistar rats afteradministration of MK-801 (0.1 mg/kg);  **  p < 0.01.  Vales, 2005; Wesierska et al., 2005). We suggest that aninteresting result of our study is, that low dose of MK-801(0.1 mg/kg) only slightly increased the locomotion (without astatistical significance), but it impaired the AAPA performancein Wistar rats.This phenomenon was observed only in Wistar rats, butLong-Evans rats solved the AAPA task successfully afteradministration of the dose of MK-801, which is in accordancewith the previous study(Stuchlik etal., 2004). The higher dosesofMK-801 (0.2and0.3 mg/kg)may haveinducedthecognitivedeficit in AAPA task; however, it was masked by hyperlocomo-tion and motor deficit.Working memory version of Morris water maze was chosenas the second approach to measure cognitive function in thepresented animal model of schizophrenia-like behaviour. Theinability to solve the working version of MWM task wasobserved after administration of higher doses of MK-801 (0.2and 0.3 mg/kg). The latencies after administration of bothmoderate and high doses of MK-801 were 60 s, the animalswere not able to find the platform at all, which suggests,together with visual observations, a profound motor impair-ment. The low dose of MK-801 (0.1 mg/kg) did not producedeficit in working memory version of the MWM, whencompared to the controls. However, we found a differencebetweenstrains after administrationof 0.1 mg/kg ofMK-801 inthe MWM. Similar differences between Long-Evans andWistar rats in control conditions were published earlier (Hortet al., 2000). This particular inter-strain difference may berelated to the fact that albinism isassociated with a deficit inthevisual system (Creel et al., 1970) and consequently with poorperformance in visual orientation tests. It is thus possible thatvisual deficit in the Wistar rats contributed to their overalldeficit in the MWM. However, Wistar rats are able to useefficientlyallotheticnavigationsimilarlytoLong-Evansrats,ascan be seen in the AAPA task, which suggests that they mighthave lower navigational potential in the MWM.Nevertheless,itmustbe emphasized that navigationintheMWM requiresmoreprecise vision than in the AAPA (consider the small size of theescape platform relatively to the 60 8  sector in the AAPA).Our previous study showed that administration of MK-801(0.1 mg/kg) disrupted reference memory version of MWM task in Long-Evans rats (Stuchlik et al., 2004). It seems thatadministration of MK-801 preferentially deteriorated referencememory before working memory in Long-Evans rats.Unfortunately we have not any comparison in Wistar rats.Considering that we failed to find an impairment of theworkingmemoryinthe MWM after the lowest doseof MK-801, it mightseem that subchronic administration of MK-801 is not optimalmodel of cognitive deficit in schizophrenia, because a workingmemory deficit has been observed in patients with schizo-phrenia and their first relatives (Glahn et al., 2003; Conklinet al., 2005). However, Steele and Morris (1999) demonstrated that blockade of NMDA receptors does not influence pureworkingmemoryinthe MWM,which isin accordancewith ourresult.Moreover,wedetectedadeficitincognitivecoordinationin the AAPA task after the low dose of MK-801, which left theworking memory in the MWM intact. It thus appears that theAAPA task is a suitable tool for investigating cognitivedifficulties related to schizophrenic-like behaviour, which is inaccordance with the results of other studies (Wesierska et al.,2005; Olypher et al., 2006).To sum up, it is suggested that using Wistar rats and theAAPA or similar task is a plausible way for next researchrelated to cognitive deficit using similar pharmacologicalmodel of the schizophrenia-like behaviour. In the workingversion of MWM task, contrarily to AAPA task, we observedstrain differences in rats treated with the lowest dose of MK-801. Acknowledgements We would like to express our gratitude to Dr. J. Bures forcriticalreadingofthemanuscriptandhisinspiringcomments,toJ. Kenney for the language check and to A. Zahalka and M.Fialova for their substantial technical assistance. 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