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Neuropharmacology 64 (2013) 357e364

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Neuropharmacology

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Quetiapine ameliorates stress-induced cognitive inflexibility in rats

Agnieszka Nikiforuk*

Department of Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland

a r t i c l e i n f o

Article history:Received 25 March 2012Received in revised form19 June 2012Accepted 20 June 2012

Keywords:QuetiapineAttentional set-shiftingStressPrefrontal cortexa1-AdrenoceptorsSelective serotonin reuptake inhibitors

* Institute of Pharmacology, Polish Academy of31-343 Krakow, Poland. Tel.: þ48 12 6623374; fax: þ

E-mail address: nikifor@if-pan.krakow.pl.

0028-3908/$ e see front matter � 2012 Elsevier Ltd.http://dx.doi.org/10.1016/j.neuropharm.2012.06.042

a b s t r a c t

The antidepressant action of quetiapine has been demonstrated in clinical and preclinical studies.Nevertheless, little is known about its effectiveness in the treatment of frontal-like cognitive distur-bances that may be associated with stress-related disorder.

Therefore, the aim of the present study was to investigate whether quetiapine would prevent and/orreverse stress-induced cognitive impairments in a rat model of prefrontal cortex (PFC)-dependentattentional set-shifting task (ASST). Because quetiapine augmentation to selective serotonin reuptakeinhibitors (SSRIs) has recently been proven to be beneficial in neuropsychiatric disorders, a separateexperiment was designed to assess the impact of combined administration of inactive doses of quetia-pine and escitalopram on ASST performance in rats.

According to our previous studies, 1 h daily exposure to restraint stress for 7 days significantly andspecifically impaired extra-dimensional (ED) set-shifting ability of rats. Quetiapine (2.5 mg/kg, PO) givento rats prior to the restraint sessions completely prevented this stress-induced cognitive inflexibility.Similar effect was demonstrated after pretreatment with the a1-adrenoceptor antagonist, prazosin(1 mg/kg, IP). Moreover, acute administration of quetiapine before the test reversed set-shifting deficitsin stressed rats (0.63, 1.25 and 2.5 mg/kg, PO) and improved ED performance of cognitively unimpairedcontrol animals (1.25 and 2.5 mg/kg, PO). Finally, the combined administration of inactive doses ofquetiapine (0.63 and 0.3 mg/kg in control and stressed rats, respectively) and escitalopram (0.3 mg/kg,IP) facilitated set-shifting performance in either control or stressed rats.

In conclusion, quetiapine administration either prevented or reversed stress-induced cognitiveinflexibility in rats. In addition to promoting of set-shifting by itself, quetiapine also enhanced theprocognitive efficacy of escitalopram. The potential contribution of the antagonism at a1-adrenoceptorsto the mechanisms underlying the protective action of quetiapine requires further evaluation.

These findings may have therapeutic implications for the treatment of frontal-like disturbances,particularly cognitive inflexibility, in stress-related psychiatric disorders.

This article is part of a Special Issue entitled ‘Cognitive Enhancers’.� 2012 Elsevier Ltd. All rights reserved.

1. Introduction

Quetiapine is the only atypical antipsychotic approved by the USFood and Drug Administration (FDA) for use as monotherapy inboth the manic and depressive phases of Bipolar Disorder (Suppeset al., 2010) as well as adjunctive therapy in Major DepressiveDisorder (MDD) (Pae et al., 2010). Moreover, quetiapine demon-strated efficacy as monotherapy in the treatment of patients withMDD (Pae et al., 2010). The antidepressant-like action of quetiapinehas also been suggested in preclinical studies. Indeed, quetiapineprevented the anhedonic state in rats exposed to the chronic mild

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stress protocol (Orsetti et al., 2007) and the major metabolite ofquetiapine, N-desalkylquetiapine, exerted antidepressant-likeeffects in the tail suspension test in mice (Jensen et al., 2008).

Although the procognitive action of quetiapine has beendemonstrated in either animal models of schizophrenia (Nikiforukand Popik, 2012; Tanibuchi et al., 2009) or schizophrenic patients(Purdon et al., 2001), little is known about effectiveness of the drugagainst frontal-like cognitive disturbances that may be associatedwith depressive disorder. Depressed patients demonstrate impair-ments in psychological tasks thought to reflect executive prefrontalfunctions (Channon, 1996; Merriam et al., 1999). Particularly, defi-cits reflecting reduced cognitive flexibility have been demonstratedindependently of the disease subtype and subjects’motivation, andmight persist after the remission of other clinical symptoms (Austinet al., 1992; Robinson et al., 2006).

A. Nikiforuk / Neuropharmacology 64 (2013) 357e364358

Flexibility in modifying behavior in response to the alteringrelevance of stimuli may be assessed in rodents in the attentionalset-shifting task (ASST) (Birrell and Brown, 2000). In this paradigm,rats must select a bowl containing food reward, based on the abilityto discriminate the odors and themedia covering the bait. The ASSTrequires rats to initially learn a rule and to form an attentional setwithin the same stimulus dimension. At the extra-dimensionalshift (ED), animals must switch their attention to a new, previ-ously irrelevant stimulus dimension and, for example, discriminatebetween the odors and no longer between the media covering thebait. The ED phase, considered to be an index of cognitive flexibility,is impaired by the lesion of the medial prefrontal cortex (mPFC)(Birrell and Brown, 2000).

Because prolonged stress has been regarded as a major riskfactor for depression, stress-based animal models representa useful instrument to mimic depressive-like symptomatology(Anisman andMatheson, 2005). In particular, the repeated restraintstress produced morphological (Cook and Wellman, 2004; Radleyet al., 2006), physiological (Cerqueira et al., 2007; Liu andAghajanian, 2008) and functional (Liston et al., 2006) alternationsin the rat mPFC, and thereforemay provide an appropriatemodel tostudy clinically relevant frontal-like cognitive deficits. Our previousstudy demonstrated that rats restrained for 1 h daily for 7consecutive days exhibited a long-lasting (up to 3 weeks) mPFC-dependent cognitive deficit as indicated by the selective impair-ment of ED set-shifting in the ASST (Nikiforuk and Popik, 2011).Therefore, the first aim of the present study was to investigatewhether quetiapine administration prior to restraint sessionswould prevent the stress-induced set-shifting deficit as assessed inthe ASST task in rats. Our previous study demonstrated that acuteadministration of quetiapine before testing reversed the ED set-shifting deficit in the N-methyl-D-aspartate receptor (NMDAR)-based rat model of schizophrenia (Nikiforuk and Popik, 2012).Therefore, a separate experiment was conducted to evaluate theeffectiveness of acute treatment with quetiapine in alleviatingstress-induced cognitive inflexibility.

Experimental data suggest that a1-adrenoceptor stimulation inthe PFC contributes to stress-induced impairments in PFC cognitivefunctions (Birnbaum et al., 1999). Consequently, high affinity ofquetiapine for the a1-adrenoceptor (Richelson and Souder, 2000)suggests that its protective action against the stress-induced EDdeficit may be due to antagonism at the a1-adrenoceptor. To furtherexplore this hypothesis, the next experiment investigated whetherpretreatment with the a1-adrenoceptor antagonist, prazosin,before each stress session would prevent cognitive inflexibility.

The combination of quetiapine with selective serotoninreuptake inhibitors (SSRIs) has recently been proven to bebeneficial in neuropsychiatric disorders, such as depressionand schizophrenia (Chertkow et al., 2009; Devarajan et al., 2006).Nevertheless, little is known about the influence of thisaugmentation strategy on cognitive functioning. Thus, the lastexperiment was designed to assess the impact of combinedadministration of inactive doses of quetiapine and escitalopramon ASST performance in rats.

2. Materials and methods

2.1. Animals

Male SpragueeDawley rats (Charles River, Germany) weighing 250e280 g onarrival were used in this study. They were housed in a temperature- (21 �1 �C) andhumidity- (40e50%) controlled colony room under a 12/12-h light/dark cycle (lightson at 06:00 h). Individual housing was maintained for the entire duration of theexperiment. For one week prior to testing, rats were mildly food restricted (15 g offood pellets per day). Behavioral testing was performed during the light phase of thelight/dark cycle. The experiments were conducted in accordancewith the NIH Guide

for the Care and Use of Laboratory Animals and were approved by the EthicsCommittee for Animal Experiments, Institute of Pharmacology.

2.2. Restraint stress procedure

The stress paradigm consisted of 1-h daily restraint stress for 7 consecutive days(Nikiforuk and Popik, 2011). Rats were transferred from a housing facility to thestress-room, separate from the testing-room. Animals were placed into perforatedplastic tubes (6.5 cm inner diameter) of adjustable length. The restraint allowed fornormal breathing and limited movements of the head and the limbs. After the stresssession, animals were removed from the restrainers and returned to their homecages for a 1-h rest period before having been transported back to the housingfacility. The rats were restrained between 13:00 and 16:00 h. The non-restrainedcontrols were handled daily for 7 consecutive days.

This stress procedure has previously been shown to produce a long-lasting (atleast up to 21 days) impairment of ED set-shifting (Nikiforuk and Popik, 2011). Toavoid the acute effects of restraint exposure and to be able to evaluate the long-termconsequences of repeated stress, the current ASST experiments were performed on14th day after the last stress session. Animals were left undisturbed during thisperiod, except for the last 5 days before the start of the testing procedure when allanimals were handled daily.

2.3. Attentional set-shifting

2.3.1. ApparatusTesting was conducted in a modified wire rat housing cage (length-

�width � height: 42 cm � 32 cm � 22 cm) with a white plywood wall dividing halfof the length of the cage into two sections (Nikiforuk and Popik, 2011, 2012). Duringtesting, one ceramic digging pot (internal diameter of 10.5 cm and a depth of 4 cm)was placed in each section. Each pot was defined by a pair of cues along with twostimulus dimensions. To mark each pot with a distinct odor, 5 ml of a flavoringessence (Dr. Oetker�, Poland) was applied on a piece of blotting paper fixed to theexternal rim of the pot immediately prior to use. A different pot was used for eachcombination of diggingmedium and odor; only one odor was ever applied to a givenpot. The bait (one-third of a Honey Nut Cheerio, Nestle�) was placed at the bottom ofthe “positive” pot and buried in the digging medium. A small amount of powderedCheerio was added to the digging media in the unbaited pot to prevent the rat fromtrying to detect the buried reward by smell.

2.3.2. Attentional set shifting: procedureThe procedure was adopted from Birrell and Brown (2000) and entailed three

days for each rat.Day 1, habituation: rats were habituated to the testing area and were trained to

dig in the pots filled with sawdust to retrieve the food reward. Rats were transportedfrom the housing facility to the testing room where they were presented with oneunscented pot (filled with several pieces of cereal) in their home cages. After the ratshad eaten the Cheerio from the home cage pot, they were placed in the apparatusand given three trials to retrieve the reward from both of the sawdust-filled baitedpots. With each exposure, the bait was covered with an increasing amount ofsawdust.

Day 2, training: rats were trained on a series of simple discriminations (SD) toa criterion of six consecutive correct trials. For these trials, rats had to learn toassociate the food reward with an odor cue (e.g., arrack vs. orange, both pots werefilled with sawdust) and/or a digging medium (e.g., plastic balls vs. pebbles, noodor). All rats were trained using the same pairs of stimuli. The positive and negativecues for each rat were presented randomly and equally. These training stimuli werenot used again in later testing trials.

Day 3, testing: rats performed a series of discriminations in a single test session.The first four trials at the beginning of each discrimination phase were a discoveryperiod (not included in the six criterion trials). In subsequent trials, an incorrectchoice was recorded as an error. Digging was defined as any distinct displacement ofthe digging media with either the paw or the nose; the rat could investigatea digging pot by sniffing or touching without displacing material. Testing wascontinued at each phase until the rat reached the criterion of six consecutive correcttrials, after which testing proceeded to the next phase.

In the simple discrimination (SD) involving only one stimulus dimension, thepots differed along one of two dimensions (i.e., a digging medium). For thecompound discrimination (CD), the second (irrelevant) dimension (i.e., an odor) wasintroduced but the correct and incorrect exemplars of the relevant dimensionremained constant. For the reversal of this discrimination (Rev 1), the exemplars andrelevant dimension were unchanged but the previously correct exemplar was nowincorrect and vice versa. The intra-dimensional (ID) shift was then presented,comprising new exemplars of both the relevant and irrelevant dimensions with therelevant dimension remaining the same as previously. The ID discrimination wasthen reversed (Rev 2) so that the formerly positive exemplar became the negativeone. For the extra-dimensional (ED) shift a new pair of exemplars was again intro-duced, but this time a relevant dimension was also changed. Finally, the last phasewas the reversal (Rev 3) of the ED discrimination problem. The exemplars werealways presented in pairs and varied so that only one animal within each treatment

Fig. 1. Schematic diagram of the experimental design. Details described in Materialsand methods.

A. Nikiforuk / Neuropharmacology 64 (2013) 357e364 359

group received the same combination. The following pairs of exemplars were used:Pair 1: odor: lemon vs. almond, medium: cotton wool vs. crumpled tissue; Pair 2:odor: spicy vs. vanilla, medium: metallic filler vs. shredded paper; and Pair 3: odor:rum vs. cream, medium: clay pellets vs. silk. The assignment of pairs of exemplars tothe stages of the ASST and the exemplar’s designation as being positive or negativein a given pair were randomized. Table 1 outlines the progression through ASSTphases.

2.4. Experimental design

The present study consisted of four independent experiments (a schematicdiagram of the experimental design is shown in Fig. 1). Experiment 1 was conductedto determine the influence of quetiapine administration prior to the restraint onstress-induced ASST deficits. Quetiapine (0 or 2.5 mg/kg) was administered to ratsper os (PO) 120 min before the restraint during 7 daily stress sessions (n ¼ 6 rats pergroup). Animals were submitted to the ASSTon the 14th day after stress termination.Unstressed controls received quetiapine or vehicle for 7 consecutive days in thehousing facility and were tested on 14th day after the last drug injection (n ¼ 6 ratsper group). Experiment 2 aimed to evaluate the effectiveness of prazosin pretreat-ment and was performed according to the same schedule as experiment 1. Prazosin(0 or 1 mg/kg) was administered to rats intraperitoneally (IP) 60 min before eachstress session (n ¼ 6 rats per group). In experiment 3, the effect of acute adminis-tration of quetiapine before testing was evaluated in both stressed and unstressedrats. Animals were restrained for 1 h daily during 7 days and the test was performedon the 14th day after the last stress session. Quetiapine (0, 0.63, 1.25 or 2.5 mg/kg,PO) was given 120 min prior to the beginning of the task (n ¼ 6 rats per group).Unstressed controls were housed and drug-treated according to the same experi-mental schedule (n ¼ 6 rats per group). The aim of experiment 4 and experiment 5was to determine the effects of coadministration of an inactive dose of quetiapine(0.63 mg/kg in control and 0.3 mg/kg in stressed rats) with an inactive dose ofescitalopram (0.3 mg/kg in both control and stressed rats) in control (n ¼ 8 rats pergroup) and stressed rats (n ¼ 6 rats per group), respectively. Quetiapine (PO) andescitalopram (IP) were given 120 and 30 min before test, respectively.

Doses and injection schedules were chosen based on our previously reporteddata (Nikiforuk and Popik, 2011; Nikiforuk, 2012).

2.5. Drugs

Quetiapine (Sigma Aldrich, Poznan, Poland) was suspended in 0.5% methylcel-lulose. Escitalopram (H. Lundbeck, Copenhagen, Denmark) and prazosin (AscentScientific, Bristol, UK) were dissolved in a sterile physiological saline.

2.6. Data analysis

The number of trials required to achieve the criterion of 6 consecutive correctresponses was recorded for each rat and for each discrimination phase. Data werecalculated using three-way mixed-design ANOVAs. Post hoc comparisons wereperformed using NewmaneKeuls test. The alpha value was set at p < 0.05. The datafulfilled the criteria for normal distribution. Statistical analyses were performedwith the use of Statistica 7.0 for Windows.

Table 1Progression through the attentional set-shifting task.

Phase Relevant dimension Discrimination

SD Medium Cotton wool Crumpled tissueCD Medium Cotton wool Crumpled tissue

Lemon AlmondRev 1 Medium Cotton wool Crumpled tissue

Lemon AlmondID Medium Clay pellets Silk

Rum CreamRev 2 Medium Clay pellets Silk

Rum CreamED Odor Spicy Vanilla

Shredded paper Metallic fillerRev 3 Odor Spicy Vanilla

Shredded paper Metallic filler

An example of the cue combinations used in the ASST of rats that were shifted fromdigging medium to odor as the relevant dimension. Rats performed a series of 7discriminations: simple discrimination (SD), compound discrimination (CD),reversal 1 (Rev 1), intra-dimensional shift (ID), reversal 2 (Rev 2), extra-dimensionalshift (ED), reversal 3 (Rev 3). The correct exemplar (shown in bold) was paired witheither of two exemplars from the irrelevant dimension (i.e., at the CD phase, thecotton wool was paired with either lemon or almond odor, etc). In the ID and ED,there were novel pairs of exemplars of each dimension.

3. Results

3.1. Experiment 1: pretreatment with quetiapine before each stresssession

According to our previous studies (Nikiforuk and Popik, 2011;Nikiforuk, 2012), 1-h daily exposure to restraint stress for 7 dayssignificantly and specifically impaired rats’ ED set-shifting ability asindicated by an increased number of trials to criterion during thisphase (Fig. 2; mean trials to criterion (TTC) for control and stressedgroups were 17.8 � 0.4 and 28.3 � 1.1, respectively). Quetiapine(2.5 mg/kg) given to rats prior to restraint sessions completelyprevented the stress-induced deficit in ED set-shifting performance(mean TTC for quetiapine-pretreated stressed rats was 17.7 � 1.7).The drug treatment did not affect performance of the unstressedcontrol group (mean TTC for quetiapine-pretreated control rats was17.1 � 0.3).

A three-waymixed design ANOVA revealed the following values:stress: F(1,20) ¼ 42.28, p < 0.001; quetiapine: F(1,20) ¼ 25.58,p < 0.001; stress � quetiapine: F(1,20) ¼ 42.28, p < 0.001; discrim-ination: F(6, 120) ¼ 216.80, p < 0.001; stress � discrimination:F(6,120) ¼ 7.43, p < 0.001; quetiapine � discrimination:F(6,120) ¼ 11.84, p < 0.001; stress � quetiapine � discrimination:F(6,120) ¼ 7.43, p < 0.001.

3.2. Experiment 2: pretreatment with prazosin before each stresssession

As illustrated in Fig. 3, rats treated with prazosin (1 mg/kg)before each stress exposure achieved the criterion during the ED

Fig. 2. The effect of quetiapine administration prior to the restraint on the stress-induced deficit in the attentional set-shifting task in rats. Animals were exposed torestraint stress for 1 h daily for 7 days. Quetiapine (0 or 2.5 mg/kg, PO) was admin-istered 120 min before each stress exposure. The ASST was performed 14 days after thestress cessation. Unstressed groups were treated according to the same experimentalschedule (N ¼ 6 rats per group). Results represent the mean � S.E.M. of the number oftrials required to reach the criterion of 6 consecutive correct trials for each of thediscrimination phases. Symbols: ***p < 0.001 vs. ED performance in the unstressedvehicle-treated group, ###p < 0.001 vs. ED performance in the stressed vehicle-treated group, NewmaneKeuls post-hoc test.

A. Nikiforuk / Neuropharmacology 64 (2013) 357e364360

stage in fewer trials compared to the vehicle-treated stressed group(mean TTC for vehicle- and prazosin-pretreated stressed groupswere 31.2 � 0.8 and 19.0 � 2.1, respectively). Moreover, EDperformance of the prazosin-pretreated stressed group did notdiffer from those of vehicle-pretreated unstressed rats (mean TTCfor vehicle þ no-stress group was 20.0 � 1.7). There was no drugeffect on unstressed control group’s performance (mean TTC forprazosin þ no-stress group was 18.7 � 1.0).

A three-way mixed design ANOVA revealed the followingvalues: stress: F(1,20) ¼ 4.57, p < 0.05; prazosin: F(1,20) ¼ 14.28,

Fig. 3. The effect of prazosin administration prior to the restraint on the stress-induceddeficit in the attentional set-shifting task in rats. Animals were exposed to restraintstress for 1 h daily for 7 days. Prazosin (0 or 1 mg/kg, IP) was administered 60 minbefore each stress exposure. The ASST was performed 14 days after the stress cessation.Unstressed groups were treated according to the same experimental schedule (N ¼ 6rats per group). Results represent the mean � S.E.M. of the number of trials required toreach the criterion of 6 consecutive correct trials for each of the discrimination phases.Symbols: ***p < 0.001 vs. ED performance in the unstressed vehicle-treated group,###p < 0.001 vs. ED performance in the stressed vehicle-treated group, New-maneKeuls post-hoc test.

p< 0.01; stress� prazosin: F(1,20)¼ 8.49, p< 0.01; discrimination:F(6,120) ¼ 170.50, p < 0.001; stress � discrimination:F(6,120) ¼ 7.28, p < 0.001; prazosin � discrimination:F(6,120) ¼ 9.15, p < 0.001; stress � prazosin � discrimination:F(6,120) ¼ 5.49, p < 0.001.

3.3. Experiment 3: acute administration of quetiapine before testing

Acute administration of quetiapine (0.63, 1.25 and 2.5 mg/kg)reversed the stress-induced deficit in ED set-shifting performance(Fig. 4; mean TTC for vehicle-treated stressed group was 31.7 � 1.1whereas for quetiapine-treated stressed groups the followingvalues were noted: 20.8� 2.1 (0.63 mg/kg), 12.5� 2.0 (1.25 mg/kg),10.7 � 2 (2.5 mg/kg)). Stressed rats that received quetiapine atdoses of 1.25 and 2.5 mg/kg also achieved the criterion during theED stage in fewer trials compared to the vehicle-treated unstressedgroup (mean TTC for vehicle þ no-stress group was 19.7 � 0.9).Additionally, quetiapine administration (1.25 and 2.5 mg/kg)improved ED set-shifting in vehicle-treated unstressed rats (meanTTC for control rats treated with quetiapine were 11.8 � 1.6(1.25 mg/kg) and 9.3 � 1.3 (2.5 mg/kg)). Quetiapine did not affectany other discrimination phase in either control or restrained rats.

A three-way mixed design ANOVA revealed the followingvalues: stress: F(1,40)¼ 12.40, p< 0.01; quetiapine: F(3,40)¼ 17.01,p < 0.001; stress � quetiapine: F(3,40) ¼ 3.38, p < 0.05; discrimi-nation: F(6,240) ¼ 125.42, p < 0.001; stress � discrimination:F(6,240) ¼ 3.84, p < 0.01; quetiapine � discrimination:F(18,240) ¼ 16.79, p < 0.001; stress � quetiapine � discrimination:F(18,240) ¼ 2.32, p < 0.01.

3.4. Experiment 4: coadministration of quetiapine and escitalopramin control rats

As shown in Fig. 5, joint administration of inactive doses ofquetiapine (0.63 mg/kg) and escitalopram (0.3 mg/kg) to controlrats reduced the number of trials to criterion in the ED phase ascompared to the vehicle þ vehicle-treated group and to thevehicle þ escitalopram-treated group (mean TTC for vehicle- andescitalopram-treated groups were 20.6 � 1.2 and 19.8 � 1.2,respectively, whereas for quetiapine þ escitalopram-treated groupwas 11.1 � 1.3). Additionally, quetiapine þ escitalopram treatmentsignificantly decreased the number of trials in the Rev 1 phase(mean TTC: 7.6 � 1.0) as compared with the vehicle þ vehiclecondition (mean TTC: 11.6 � 0.9).

A three-way mixed design ANOVA revealed the followingvalues: quetiapine: F(1,28) ¼ 10.77, p < 0.01; escitalopram:F(1,28)¼ 12.45, p< 0.01; quetiapine� escitalopram: F(1,28)¼ 4.40,p < 0.05; discrimination: F(6, 168) ¼ 143.72, p < 0.001;quetiapine � discrimination: F(6,168) ¼ 6.20, p < 0.001;escitalopram � discrimination: F(6,168) ¼ 6.55, p < 0.001;quetiapine � escitalopram � discrimination: F(6,168) ¼ 4.35,p < 0.001.

3.5. Experiment 5: coadministration of quetiapine and escitalopramin stressed rats

Coadministration of inactive doses of quetiapine (0.3 mg/kg)and escitalopram (0.3 mg/kg) to stressed rats reduced the numberof trials to criterion in the ED phase as compared to thevehicle þ vehicle-treated group and to the vehicle þ escitalopram-treated group (Fig. 6; mean TTC for vehicle- and escitalopram-treated groups were 30.7 � 0.9 and 29.7 � 1.8, respectively,whereas for quetiapine þ escitalopram-treated group was7.8 � 1.0). Additionally, quetiapine þ escitalopram treatmentsignificantly decreased the number of trials in the Rev 1 phase

Fig. 4. The effect of acute administration of quetiapine on the stress-induced deficit in the attentional set-shifting task in rats. Animals were exposed to restraint stress for 1 h dailyfor 7 days. The ASST was performed 14 days after the stress cessation. Quetiapine (0, 0.63, 1.25 or 2.5 mg/kg, PO) was administered 120 min before testing (N ¼ 6 rats per group).Results represent the mean � S.E.M. number of trials required to reach the criterion of 6 consecutive correct trials for each of the discrimination phases. Symbols: ***p < 0.001 vs. EDperformance in the unstressed vehicle-treated group, ###p < 0.001 vs. ED performance in the stressed vehicle-treated group, NewmaneKeuls post-hoc test.

A. Nikiforuk / Neuropharmacology 64 (2013) 357e364 361

(mean TTC: 7.0 � 0.8) as compared with the vehicle þ vehiclecondition (mean TTC: 11.7 � 1.3).

A three-way mixed design ANOVA revealed the followingvalues: quetiapine: F(1,20) ¼ 27.26, p < 0.001; escitalopram:F(1,20) ¼ 38.69, p < 0.001; quetiapine � escitalopram:F(1,20) ¼ 18.85, p < 0.001; discrimination: F(6, 120) ¼ 294.30,p< 0.001; quetiapine� discrimination: F(6,120)¼ 23.35, p< 0.001;escitalopram � discrimination: F(6,120) ¼ 33.34, p < 0.001;

Fig. 5. The effect of coadministration of quetiapine and escitalopram on control rats’performance on the attentional set-shifting task. Quetiapine (0.63 mg/kg, PO) andescitalopram (0.3 mg/kg, IP) were administered 120 and 30 min, respectively, beforetesting (N ¼ 8 rats per group). Results represent the mean � S.E.M. number of trialsrequired to reach the criterion of 6 consecutive correct trials for each of the discrim-ination phases. Symbols: ***p < 0.001 vs. ED performance in the vehicle þ vehicle-treated group, ###p < 0.001 vs. ED performance in the ESC þ vehicle-treatedgroup, þþp < 0.01 vs. Rev 1 performance in the vehicle þ vehicle-treated group.NewmaneKeuls post-hoc test.

quetiapine � escitalopram � discrimination: F(6,120) ¼ 29.95,p < 0.001.

4. Discussion

The present study revealed that quetiapine administrationbefore each restraint session prevented stress-induced cognitive

Fig. 6. The effect of coadministration of quetiapine and escitalopram on stressed rats’performance on the attentional set-shifting task. Animals were exposed to restraintstress for 1 h daily for 7 days. The ASST was performed 14 days after the stresscessation. Quetiapine (0.3 mg/kg, PO) and escitalopram (0.3 mg/kg, IP) were admin-istered 120 and 30 min, respectively, before testing (N ¼ 6 rats per group). Resultsrepresent the mean � S.E.M. number of trials required to reach the criterion of 6consecutive correct trials for each of the discrimination phases. Symbols: ***p < 0.001vs. ED performance in the vehicle þ vehicle-treated group, ###p < 0.001 vs. EDperformance in the ESC þ vehicle-treated group, þþp < 0.01 vs. Rev 1 performance inthe vehicle þ vehicle-treated group. NewmaneKeuls post-hoc test.

A. Nikiforuk / Neuropharmacology 64 (2013) 357e364362

inflexibility. Similar effect was demonstrated after prazosinpretreatment. Moreover, acute administration of quetiapine beforetesting reversed set-shifting deficits in stressed rats and improvedED performance of cognitively unimpaired control animals. Finally,combined administration of inactive doses of quetiapine and esci-talopram facilitated cognitive flexibility in control and stressed rats.

Recent preclinical data have already suggested the procognitiveaction of quetiapine. In reference to the present study, quetiapinereversed the ED set-shifting impairment induced by subchronicadministration of ketamine to rats, the NMDAR-based model ofschizophrenia (Nikiforuk and Popik, 2012). The quetiapine’s effec-tiveness in other cognitive domains was also demonstrated becausethe drug reversed the deficit caused by repeated administration ofanother NMDAR antagonist, phencyclidine, in a novel objectrecognition task in mice (Tanibuchi et al., 2009). Nevertheless, thereported procognitive action of quetiapine was not restricted toschizophrenia-like states. Accordingly, quetiapine treatmentameliorated learning and spatial memory impairments in ratsexposed to enhanced single prolonged stress, an animal model ofpost-traumatic stress disorder (Wang et al., 2010). Quetiapine alsoalleviated spatial working and reference memory deficits ina transgenic mouse model of Alzheimer’s disease (He et al., 2009).Beneficial effects of quetiapine on cognitive functioning were alsonoted in a cerebral ischemia model (Yan et al., 2007) and ina methamphetamine-induced neurotoxicity model (He et al.,2006). The present results extend this finding by demonstratingthe efficacy of quetiapine against stress-related disturbances infrontal-dependent cognitive flexibility.

According to our previous report (Nikiforuk and Popik, 2011),repeated restraint stress selectively impaired rats’ ability toperform the ED phase of the ASST as assessed 14 days after stresscessation. This result is consistent with the study of Liston et al.,(Liston et al., 2006), who reported that the restraint-induceddecrease in dendritic arborization in the mPFC is associated withselective deficits of the ED set-shifting. However, it should be notedthat the single housing conditions, applied in the present study,may be regarded as a social isolation stressor (Stranahan et al.,2006). Thus, it cannot be excluded that restraint stress and socialisolation may additively affect rats’ performance at the ASST.

Furthermore, the administration of quetiapine before eachrestraint session prevented the stress-induced cognitive inflexi-bility. Likewise, pretreatment with the a1-adrenoceptor antagonist,prazosin, also rescued set-shifting ability of stressed rats. Given thehigh affinity of quetiapine for the a1-adrenoceptor, it might besuggested that its protective effect resulted from the antagonism ata1-adrenoceptors. However, additional experiments are requiredto support this hypothesis, since other possible mechanisms ofquetiapine’s action cannot be excluded. Firstly, quetiapine wasdemonstrated to affect hypothalamic-pituitary-adrenal (HPA) axisactivity. Specifically, quetiapine reduced nocturnal elevations ofcortisol in healthy human volunteers either following acousticstress or under undisturbed condition (Cohrs et al., 2004). More-over, pretreatment with quetiapine attenuated the immobilizationstress-induced increase in corticotropin-releasing factor mRNAexpression in the paraventricular nucleus of the hypothalamus(Park et al., 2007). The potential role of the quetiapine-evokeddown-regulation of the HPA axis response to stress in its protec-tive action in the current ASST experiment is supported by ourprevious study demonstrating that the pharmacological attenua-tion of corticosterone synthesis during stress exposure preventedstress-induced cognitive inflexibility (Nikiforuk and Popik, 2011).Alternatively, it is likely that neurotrophic and/or neuroprotectiveaction of quetiapine may participate in the beneficial effects of thisdrug against stress-induced cognitive deficits. In fact, quetiapinereversed the suppression of hippocampal neurogenesis caused by

restraint stress (Luo et al., 2005) as well as attenuated the immo-bilization stress-induced decrease in brain-derived neurotrophicfactor expression in the rat hippocampus and cortex (Park et al.,2006). Moreover, a recent study suggested that induction of glialcell-derived neurotrophic factor release by the major metabolite ofquetiapine, N-desalkylquetiapine, may contribute to the mecha-nisms of the drug action (Di Benedetto et al., 2012).

The present demonstration of the protective action of prazosinagainst cognitive inflexibility in restrained rats is in accordancewith the well-established role of a1-adrenoceptors in stress-induced impairments of prefrontal functions. Accordingly, highlevel of noradrenaline during stress exposure (Finlay et al., 1995)stimulates a1-adrenoceptors and activates the phosphatidylinosi-tol (PI) signaling pathway and protein kinase C (PKC). Consistentwith the role of a1-adrenoceptor-PKC signaling in detrimentaleffects of stress, PFC-related cognitive deficits were observed afterexposure to a pharmacological stressor, stimulation of a1-adrenoceptor, or direct activation of PKC (Arnsten et al., 1999;Birnbaum et al., 1999, 2004). Subsequently, the inhibition of eithera1-adrenoceptor or PKC restored cognitive functions (Birnbaumet al., 1999, 2004). Moreover, Hains et al. (2009) suggested thatPKC overactivity might be responsible for alterations in prefrontaldendritic morphology and cognitive functions in rats subjected tothe chronic restraint stress paradigm. Therefore, it may be assumedthat stress-evoked excessive PKC signaling, arising from a1-adrenoceptor stimulation, accounted for the ED set-shiftingdeficit in the current study. However, it should be noticed thatpathways other than PKC signaling may also contribute to thedetrimental effects of stress exposure. For example, stress-inducedcatecholamine release may impair prefrontal functions throughpotentiating cyclic adenosine monophosphate (cAMP) signaling[see for review Arnsten, 2009].

Furthermore, the present study demonstrated that acuteadministration of quetiapine prior to testing promoted cognitiveflexibility in control and stressed rats. However, the ED componentimprovement was noted primarily in stressed (the lowest effectivedose: 0.63 mg/kg) but not in the control rats, in which the drugfacilitated ED shift solving only at the higher doses, i.e., 1.25 and2.5 mg/kg.

In contrast to the potential implication of a1-adrenergicantagonism in the mechanisms by which quetiapine preventsstress-induced cognitive deficits, it remains questionable whetherthe acute blockade of those receptors could improve set-shiftingcapacity. Accordingly, the results of Lapiz and Morilak (2006) sug-gested that a1-adrenoceptor stimulation rather than blockade mayplay a role in facilitating the ASST responding. Thus it may besuggested that mechanisms other than the antagonism at a1-adrenoceptors are responsible for facilitation of cognitive flexi-bility following acute administration of quetiapine. Accordingly,recent data have indicated that the active metabolite of quetiapine,N-desalkylquetiapine, may be involved in its actions (Jensen et al.,2008). This compound was characterized as a potent inhibitor ofthe noradrenaline reuptake transporter (NET) and showed rela-tively high affinity for the serotonin 7 (5-HT-7) receptor (Jensenet al., 2008). This pharmacological profile of N-desal-kylquetiapine, already proposed to explain the antidepressantaction of quetiapine, may also account for the procognitive effectsof the drug. Indeed, it has beenwidely accepted that noradrenalinetransmission is involved in the prefrontal cortical functions relatedto attentional set-shifting. Elevation of noradrenaline neurotrans-mission in the mPFC by acute administration of the a2-adrenergicautoreceptor antagonist, atipamezole, or chronic treatment withthe NET inhibitor, desipramine, abolished set-shifting deficits inrats subjected to chronic unpredictable stress (Bondi et al., 2010).Correspondingly, our previous study demonstrated that acute

A. Nikiforuk / Neuropharmacology 64 (2013) 357e364 363

administration of desipramine reversed the stress-induced set-shifting deficit and promoted cognitive flexibility in control rats(Nikiforuk and Popik, 2011). Likewise, acute administration ofa selective antagonist of 5-HT7 receptors facilitated set-shifting incognitively unimpaired rats as well as ameliorated stress-evokedcognitive inflexibility (Nikiforuk, 2012). However, the contribu-tion of N-desalkylquetiapine to the procognitive action of quetia-pine in the present ASST experiment remains equivocal, since it isunclear if N-desalkylquetiapine is formed in rats.

Moreover, it has been proposed that the ability of atypicalantipsychotic drugs to increase dopamine level in the prefrontalcortex might underlie their potential procognitive action. Conse-quently, quetiapine has been demonstrated to increase dopaminelevel in the rat mPFC (Ichikawa et al., 2002; Pira et al., 2004;Yamamura et al., 2009). However, the lack of an effect of quetiapineon PFC dopamine release was also noted (Denys et al., 2004).Because acute administration of the dopamine reuptake inhibitor,nomifensine, was previously shown to either facilitate ED set-shifting in control rats or reverse stress-induced cognitive inflexi-bility (Nikiforuk and Popik, 2011), the quetiapine-evoked increasein dopamine levels could account for its beneficial action in theASST. Finally, quetiapine also enhanced the cortical glutamate andacetylocholine levels (Yamamura et al., 2009). The role of gluta-matergic transmission in modulating cognitive flexibility has beensuggested previously (Nikiforuk et al., 2011). Nevertheless, itremains equivocal whether cholinergic transmission plays a criticalrole in the modulation of attentional set-shifting because acetyl-choline depletion in the rat mPFC did not affect performance onthat task (McGaughy et al., 2008).

Finally, the present study showed that coadministration ofinactive doses of quetiapine and escitalopram facilitated set-shifting capacity in control and stressed rats. However, althoughthe combination of quetiapine in addition to SSRIs has been provento be beneficial in neuropsychiatric disorders including depression(Chertkow et al., 2009; Devarajan et al., 2006), the impact of thisaugmentation strategy on cognitive functions has not beensystematically addressed in either clinical trials or preclinicalmodels. Nevertheless, some reports suggest that clinical benefits ofquetiapine augmentation of SSRI antidepressant therapy mayinclude possible improvements in cognition (Olver et al., 2008).

The potential mechanism of procognitive effects followingcombined administration of quetiapine and SSRIs may be explainedby the increase in the prefrontal level of dopamine. In fact, themicrodialysis study of Denys et al. (2004) demonstrated a syner-gistic dopamine increase in the rat PFC after the combination ofquetiapine and fluvoxamine. Since the enhancement of dopami-nergic neurotransmission facilitated set-shifting in rats, thisneurochemical mechanism could account for the procognitiveeffect in the present interaction study. Alternatively, the affinity ofN-desalkylquetiapine at 5-HT7 receptors may participate in thiseffect, as our previous study revealed that joint administration ofinactive doses of a selective antagonist of 5-HT7 receptors andescitalopram enhanced ED set-shifting performance in rats(Nikiforuk, 2012). Moreover, the 5-HT7 receptor blockade has beenwidely demonstrated to augment the behavioral effects of antide-pressants in animal models [e.g., see (Wesolowska et al., 2007)].

Coadministration of quetiapine with escitalopram alsoimproved the first reversal (Rev 1) phase of the ASST. On thecontrary, neither quetiapine nor escitalopram affected the perfor-mance of rats at this stage of the task when administered alone.Given the well-documented role of serotonergic transmission inregulation of reversal learning (Clarke et al., 2005), it may bespeculated that the enhanced release of serotonin followingcombined administration of the drugs could be responsible for thiseffect. It was actually demonstrated that the combination of

quetiapine and fluvoxamine increased serotonin level in the ratbrain (Denys et al., 2004). In the latter study, however, fluvoxaminealso enhanced serotonin release when administered alone (but ata relatively high dose of 10 mg/kg).

It should be noticed that the restraint stress shifted thethreshold for quetiapine’s efficacy toward lower drug’s doses.Specifically, administration of quetiapine at a dose of 0.63 mg/kgimproved ED set-shifting in stressed rats, while having no effect onperformance of unstressed controls. Similarly, coadministration ofa relatively low dose of quetiapine (i.e., 0.3 mg/kg) with escitalo-pram improved cognitive flexibility of stressed rats. Comparableeffect was noted for quetiapine at a dose of 0.63 mg/kg when theinteraction study was conducted on unstressed control rats.Therefore, it may be concluded that the stress-induced changes inthe mPFC may underlie the hyperresponsiveness to the quetiapine-induced enhancement of set-shifting ability. However, the systemicroute of administration cannot preclude that the drug’s action inother than the mPFC brain regions is responsible for the observedeffects. In fact, ventral striatal efferents have been demonstrated tointeract with the PFC to regulate set-shifting (Floresco et al., 2006).Moreover, detrimental effects of stress may result from its complexaction onmultiple and often interacting brain regions. For example,electrophysiological studies have shown that there are reciprocalinhibitory influences between prefrontal cortex and amygdala(Perez-Jaranay and Vives, 1991; Quirk et al., 2003). Likewise, it hasbeen demonstrated that the effect of stress hormone on mPFCfunctions involves activation of basolateral amygdale neurons(Roozendaal et al., 2004).

In summary, the present study demonstrated the effectivenessof quetiapine in preventing and reversing stress-induced cognitiveinflexibility in rats. In addition to promoting set-shifting by itself,quetiapine also enhanced the procognitive efficacy of escitalopram.These findings may have therapeutic implications for the treatmentof frontal-like disturbances, particularly cognitive inflexibility, instress-related psychiatric disorders.

Acknowledgments

This work was supported by the grant POIG.01.01.02-12-004/09“Depresja - mechanizmy - terapia”, co-financed by the EuropeanUnion from the European Fund of Regional Development (EFRD).

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