Bilateral lesions of the entorhinal cortex differentially modify haloperidol- and olanzapine-induced c-fos mRNA expression in the rat forebrain

Neuropharmacology 45 (2003) 190–200www.elsevier.com/locate/neuropharm

Bilateral lesions of the entorhinal cortex differentially modifyhaloperidol- and olanzapine-inducedc-fos mRNA expression in the

rat forebrain

A. Seillier a,∗, E. Coutureaua,1, N. Thiriet b, K. Herbeauxa, J. Zwiller b, G. Di Scalaa,1,B. Will a, M. Majchrzaka

a Laboratoire de Neurosciences Comportementales et Cognitives, UMR 7521, Universite Louis Pasteur, CNRS, IFR des Neurosciences,Strasbourg, France

b Physio-pathologie du systeme nerveux, INSERM U575, Centre de Neurochimie, IFR des Neurosciences, Strasbourg, France

Received 21 January 2003; received in revised form 14 March 2003; accepted 26 March 2003

Abstract

Lesions of the entorhinal cortex are now an accepted model for mimicking some of the neuropathological aspects of schizophrenia,since evidence has accumulated for the presence of cytoarchitectonic abnormalities within this cortex in schizophrenic patients. Thepresent study was undertaken to address the functional consequences of bilateral entorhinal cortex lesions on antipsychotic-inducedc-fos expression. After a 15-day recovery period, the effect of a typical antipsychotic, haloperidol (1 mg/kg), onc-fos mRNAexpression was compared with that of an atypical one, olanzapine (10 mg/kg), in both sham-lesioned and entorhinal cortex-lesionedrats. In sham-lesioned rats, both haloperidol and olanzapine inducedc-fos expression in the caudal cingulate cortex, dorsomedialand dorsolateral caudate-putamen, nucleus accumbens core and shell and lateral septum. In addition, olanzapine, but not haloperidol,increasedc-fos expression within the central amygdala. In entorhinal cortex-lesioned rats, haloperidol-inducedc-fos expression wasmarkedly reduced in most areas. In contrast, the olanzapine-inducedc-fos expression was not altered in the nucleus accumbens shelland lateral septum of the lesioned rats. These findings reveal that entorhinal cortex lesions affectc-fos expression in a compound- andregional-dependent manner. Our results further emphasize the importance of the exploration of the mechanisms of action of antipsy-chotic drugs in the context of an associated cortical pathology. 2003 Elsevier Science Ltd. All rights reserved.

Keywords: Atypical antipsychotic;c-fos mRNA; Entorhinal cortex; Lateral septum; Nucleus accumbens; Typical antipsychotic

1. Introduction

A recent concept in the pathophysiology of schizo-phrenia proposes that this condition may be related todisturbances in the regulation of sub-cortical dopami-nergic systems by an alteration in the activity of glutam-atergic cortical afferents (Grace, 2000; Weinberger andLipska, 1995). Several studies of schizophrenic patientshave indeed reported structural abnormalities in pre-

∗ Corresponding author. Tel.:+33-39-024-1913; fax:+33-39-024-1958.

E-mail address: [email protected] (A.Seillier).

1 Present address: Laboratoire de Neurosciences Cognitives, UMR5106, Universite´ Bordeaux I, CNRS, Talence, France.

0028-3908/03/$ - see front matter 2003 Elsevier Science Ltd. All rights reserved.doi:10.1016/S0028-3908(03)00147-3

frontal cortex (Gur et al., 2000; Pierri et al., 2001), hip-pocampus (Narr et al., 2001; Zaidel et al., 1997) andentorhinal cortex (Arnold et al., 1991, 1997; Falkai etal., 2000). The functional consequences of the lesion ofthe corresponding areas in animals (integrating in somecases the supposed developmental dimension of the dis-ease, seeLipska and Weinberger, 2000, for a review)were assessed in a variety of tests showing reasonablevalidity with respect to the pathology, such as prepulseinhibition, vulnerability to stress, blocking and latentinhibition (Ellenbroek and Cools, 1990; Feldon andWeiner, 1991; Gray et al., 1991; Lipska et al., 1993). Inparticular, it has become clear that lesions of the entorhi-nal cortex disrupt prepulse inhibition (Goto et al., 2002)and latent inhibition (Coutureau et al., 1999; Oswald etal., 2002). Moreover, the deficit of latent inhibition

191A. Seillier et al. / Neuropharmacology 45 (2003) 190–200

induced by entorhinal cortex lesion is reversed by olan-zapine, but not by haloperidol (Coutureau et al., 2000;but see Yee et al., 1995). This is of particular importancesince, in rats without cortical pathology, both com-pounds are able to compensate the disruptive effect ofamphetamine on latent inhibition (Gosselin et al., 1996;Warburton et al., 1994).

The mechanisms of action of antipsychotic drugs,whether classified as typical or atypical, are essentiallystudied using electrophysiological, neurochemical, neu-roanatomical and behavioral approaches (for a review,see Arnt and Skarsfeldt, 1998); only a few studies havebeen carried out in the context of an associated corticallesion (e.g. Bardgett and Csernansky, 1996). However,studies addressing the issue of an interaction betweenantipsychotic behavioral effects and brain lesions havereported a dissociation between typical and atypicalcompounds (e.g. Bardgett et al., 1997; Lipska and Wein-berger, 1994).

The analysis of the pattern of regional c-fos expressioninduced by antipsychotics is a powerful neuroanatomicaltechnique to identify the brain targets which are likelyto contribute to their antipsychotic effects. Typical (e.g.haloperidol) and atypical (e.g. clozapine) antipsychoticdrugs induce regionally specific patterns of c-fosexpression (Fink-Jensen and Kristensen, 1994 ; Robert-son and Fibiger, 1992) which are predictive of theirclinical profiles. Indeed, typical antipsychotic-induced c-fos expression in the dorsolateral striatum is consideredto reflect their potential for producing extrapyramidalside effects, and atypical antipsychotic-induced c-fosexpression in the prefrontal cortex may be related to theirefficacy for treating negative symptoms (Robertson etal., 1994). In brain areas where both kinds of compoundsinduce c-fos expression, such as the nucleus accumbensshell, antipsychotics have been reported to target differ-ent sub-populations of neurons (Guo et al., 1998).

The aim of the present study was twofold: first tocompare the pattern of c-fos expression induced by halo-peridol to that induced by olanzapine, second to evaluatethe effect of bilateral entorhinal cortex lesions on thesepatterns. The c-fos expression was analyzed using in situhybridization in various brain structures known to con-nect with the entorhinal cortex and previously shown tobe targets of antipsychotics, namely the nucleus accum-bens, caudate-putamen, cingulate cortex, hippocampus,lateral septum and amygdala.

Portions of this work have been presented previouslyin abstract form (Seillier et al., 2000).

2. Materials and methods

2.1. Animals

Thirty-three Long-Evans male rats (275–320 g)obtained from the Centre d’Elevage Rene Janvier

(France) were used. They were housed two per cage, ina temperature controlled room (21 °C) under a 12 h–12h light–dark cycle (lights on at 8:00 am). Food and waterwere available ad libitum. Rats were allowed to becomeaccustomed to the laboratory vivarium for 1 week. Allprocedures involving animals and their care conformedto the institutional guidelines, which comply withnational (council directive 87848, 19 October 1987,Ministere de l’Agriculture et de la Foret, Service Veteri-naire de la Sante et de la Protection Animale; permission7294 to M.M., A.S. under the former’s responsibility)and international (directive 86-609, 24 November 1986,European Community) laws and policies.

2.2. Surgery

Lesions of the entorhinal cortex were performed byusing an excitotoxic, axon-sparing lesion technique pre-viously described by Coutureau et al. (1999). Anesthet-ized rats (sodium pentobarbital, i.p., 75 mg/kg) werefixed in a stereotaxic frame with the incisor bar placedsuch as Bregma was 1 mm below Lambda. Bilaterallesions of the entorhinal cortex were performed by usingmultiple injections of N-Methyl-D-Aspartate (NMDA;Sigma, 40mM in PBS, pH 7.4). NMDA was injectedthrough an injection cannula (0.28 mm o.d.) which wasconnected via polyethylene tubing to a 10 µl Exmiremicrosyringe driven by an automated syringe pump(CMA model 100). The cannula was lowered into thebrain at 6 sites under a mediolateral angle of 15° accord-ing to the following coordinates from bregma: A �8.2mm, L ±3.5 mm, V �7.5, �7, �6 mm according to theatlas of Paxinos and Watson (1998). At each site, 0.2 µlof NMDA was injected over a period of 1 min. The can-nula was left in place for 1 min after each injection.Control rats were operated similarly but no injection wascarried out. Twenty rats sustained entorhinal lesions and13 served as controls. Experiments were performed 15days after surgery. This post-lesion time point matchesthat used by Coutureau et al. (2000) for drug adminis-tration.

2.3. Drug administration

In order to minimize c-fos induction by stress, ratswere handled for 3 days before drug administration. Ani-mals were injected i.p. with either haloperidol (Sigma,1 mg/ml/kg dissolved in tartrate), olanzapine (Lilly,USA, 10 mg/5 ml/kg dissolved in lactate), or vehicle(tartrate or lactate). The selection of equivalent doses forvarious antipsychotics is difficult due to the complexityof the pharmacological actions of these drugs. Therefore,we selected the dose of olanzapine both on clinicalequivalencies set relative to a reference dose of haloperi-dol of 1mg/kg which has been used extensively (Chartoffet al., 1999; Guo et al., 1998; Merchant et al., 1996;

192 A. Seillier et al. / Neuropharmacology 45 (2003) 190–200

Pinna and Morelli, 1999) and on the basis of the reportof Robertson and Fibiger (1996) showing that olanzapineat a dose of 10 mg/kg increased c-fos expression in abroader range of brain areas than olanzapine at 5 mg/kg.

2.4. Tissue preparation

Forty-five minutes after drug administration, the ratswere killed with an overdose of sodium pentobarbital(120 mg/kg), transcardially perfused with 0.9% salinefollowed by 1% paraformaldehyde. The brains wereremoved, placed in fresh fixative (1% paraformaldehyde)for 1 h and cryoprotected in 0.1M phosphate buffer sat-ured with 15% sucrose for 24 h. The brains were thenfrozen in isopentane (�45 °C) and stored at �80 °Cbefore being sectioned using a freezing microtome(�20 °C).

Three sequential coronal sections (10 µm) were cut atapproximately the following coordinates from bregma:+4.2 mm, +1.6 mm and �2.8 mm according to the atlasof Paxinos and Watson (1998). The sections were col-lected onto gelatin-coated slides, dried and stored at �80°C. Caudal sections of the brain were also collected.They were stained with cresyl violet in order to deter-mine the location and extent of the lesion.

2.5. In situ hybridization

In situ hybridization with riboprobe for c-fos was per-formed as described previously by Thiriet et al. (1998)with [35S]uridine triphosphate (UTP)-labeled RNAprobes. Briefly, sections were delipidated, acetylated,prehybridized for 10 min at 60 °C in 50% formamide,1 × SSC (150 mM NaCl and 15 mM sodium citrate, pH7.0), dehydrated and air-dried. Thirty microliters of thelabeled probe, diluted to 50,000 dpm/µl with hybridiz-ation buffer (50% formamide, 4 × SSC, 10% dextransulphate and 10 mM dithiothreitol), was placed on tissuesections and covered with coverslips. Hybridization wascarried out overnight at 52 °C. Hybridization mediumwas then washed off and the sections were washed twicein 50% formamide, 1 × SSC at 55 °C for 1 h, followedby two washes in 2 × SSC (5 min, room temperature).Sections were incubated in a 10 mM Tris-HCl buffer(pH 8.0) containing 100 mM NaCl, 1 mM EDTA and6.10�3 U/ml RnaseA (Merck) for 30 min at 37 °C. Theslides were then rinsed, dehydrated and exposed to X-ray film (Kodak Biomax-MR) for 8 days. Sense controlswere performed, that detected no signal.

2.6. Quantification of c-fos mRNA

All data were obtained from the same in situ hybridiz-ation experiment. The autoradiograms were digitized,and the magnitude of the signal from the hybridized 35ScRNA probe was determined using an image analyzer

(Samba, Autoradiography software). For each hemi-sphere, the optical density (OD) within the brain regionsshown in Fig. 1 was measured out of the three corre-sponding successive sections (which were hybridized atthe same time and developed on the same film). In orderto correct for background expression, measurementswere done on the film adjacent to the section (where notissue was present), and the obtained values were sub-tracted from the OD value of each section. Data thusobtained were averaged providing an average signal foreach animal.

2.7. Statistical analysis

For each brain region, the average hybridization signalwas analyzed by a two-way analysis of variance(ANOVA) with Drug (vehicle, haloperidol andolanzapine) and Lesion (sham lesion and entorhinal cor-tex lesion) as factors. Differences between groups wereestablished by post-hoc comparisons using the New-man–Keuls test. For all comparisons, values of p �0.05 were considered as statistically significant.

3. Results

3.1. Verification of the lesion

After light microscopic examination, 8 rats were dis-carded from the final analysis: these rats either sustainedsome damage to neighboring structures (hippocampusCA1 in 3 rats) or an asymmetric lesion (in 3 rats), orshowed extensive sparing of the entorhinal cortex (in 2rats). The extent and selectivity of the lesions werebroadly consistent among groups and resemble those ofa typical lesion which is illustrated in Fig. 2. Lesionswere centered around –7.64 mm from bregma, where thedamage was the most extensive (�55% of the entorhinalcortex) and included both deep and superficial layers ofboth medial and lateral entorhinal cortex. Damagesgradually decreased rostrally and caudally to this pointand did not extend more rostrally than –6.3 mm frombregma and caudally than –8.72 mm from bregma. Atthe most rostral levels, the lesion comprised some partsof the caudal lateral components of the entorhinal cortexand some restricted parts of the ventral and caudalcomponents of the subiculum. At more caudal levels,most of the superficial and deep layers of the medialentorhinal cortex were damaged. At the most caudal lev-els, the lesions comprised the most superficial layers ofthe medial entorhinal cortex whereas the deep layerswere spared. No damage was observed in control rats.

3.2. c-fos mRNA expression

The hybridization signal differed across the brainregions considered (data not shown), but no difference


Fig. 1. Schematic representation of areas sampled for c-fos mRNA quantitative analysis on plates from the atlas of Paxinos and Watson (1998).Boxes indicate the sampled areas in the cingulate cortex at rostral (1) and caudal (2) levels, the caudate-putamen at dorsomedial (3) and dorsolateral(4) levels, the nucleus accumbens at core (5) and shell (6) levels and the septum at lateral level (7). The hippocampus was sampled in CA1 (8),CA3 (9) and dentate gyrus (10) subdivisions, and the amygdala in central (11) and lateral (12) nuclei.

Fig. 2. A: Photomicrographs of Cresyl violet stained frontal sections (approximately 7.6 mm posterior to bregma) of the brain of a sham-lesionedrat and of an entorhinal cortex-lesioned rat. Photomicrographs were taken in the area delimited on the schematic representation (adapted fromPaxinos and Watson, 1998) shown on the left part of the figure. The extent of the lesion is marked by arrows. Inserts are cells viewed under ahigher magnification. MEnt, medial entorhinal cortex; LEnt, lateral entorhinal cortex. B: Schematic representations of the extent of a representativeentorhinal cortex lesion. Coordinates of the frontal sections are indicated with reference to bregma according to the stereotaxic atlas of Paxinosand Watson (1998).


between tartrate and lactate was detected, so the dataobtained after tartrate or lactate administration werepooled. Because haloperidol administration was not suc-cessful in one lesioned rat, the final group sizes were asfollows: sham-vehicle (n = 5), sham-haloperidol (n = 4),sham-olanzapine (n = 4), entorhinal-vehicle (n = 4),entorhinal-haloperidol (n = 3), entorhinal-olanzapine (n= 4).

Only the brain regions in which ANOVAs revealedsignificant effects of main factors and/or interaction areillustrated (Figs. 3 and 4); for each of these regions, theaverage hybridization signals obtained in vehicle, halop-eridol- and olanzapine-treated groups are shown in theleft part of Fig. 4 for sham-lesioned rats and in the rightpart of the figure for the entorhinal cortex-lesioned rats.The results obtained in the other brain areas investigatedare reported in Table 1.

For all investigated brain areas, vehicle injection pro-duced a similar pattern of hybridization signal in sham-and entorhinal cortex-lesioned rats, thus indicating thatthe lesion per se did not modify c-fos mRNA expression.

For the caudal cingulate cortex (Figs. 3 and 4),ANOVA revealed significant effects of Drug(F(2,16) = 28.09, p � 0.0001), Lesion (F(1,16) =22.33, p � 0.001), as well as a significant interactionbetween these two factors (F(2,16) = 7.10, p � 0.01).In sham-lesioned rats, post hoc tests showed that acuteinjections of haloperidol and olanzapine significantlyincreased c-fos levels (p � 0.001 in both cases). Inentorhinal cortex-lesioned rats, olanzapine but not halop-eridol significantly increased c-fos mRNA expression

Fig. 3. Negative prints of in situ hybridization autoradiograms show-ing mRNA expression of c-fos in response to acute injection of halop-eridol (1 mg/kg) or olanzapine (10 mg/kg) in a sham-lesioned rat andan entorhinal cortex-lesioned rat. Rat brain coronal sections (10 µm)were taken at the level of the striatum (approx 1.6 mm anterior tobregma).

(p � 0.05). Moreover, both haloperidol and olanzapine-induced c-fos expression were significantly lower inentorhinal cortex-lesioned rats compared to sham-lesioned rats (p � 0.001 and p � 0.01, respectively).

For the rostral cingulate cortex (Table 1), ANOVAfailed to reveal significant effects of Drug (F(2,15) =0.51, p = 0.61), Lesion (F(1,15) = 0.60, p = 0.45) orinteraction between these factors (F(2,15) = 1.25, p =0.31).

For the dorsomedial caudate-putamen (Figs. 3 and 4),ANOVA revealed significant effects of Drug (F(2,16)= 11.69, p � 0.001), Lesion (F(1,16) = 12.11, p �0.01) as well as a significant interaction between Drugand Lesion (F(2,16) = 4.49, p � 0.05). In sham-lesionedrats, post hoc tests showed that acute injections of halop-eridol and olanzapine significantly increased c-fos levels(p � 0.01 in both cases). In entorhinal cortex-lesionedrats, neither haloperidol nor olanzapine significantlymodified c-fos mRNA expression. Moreover, haloperi-dol-induced c-fos expression was significantly loweredin these rats as compared to sham-lesioned rats (p �0.01).

For the dorsolateral caudate putamen (Figs. 3 and 4),ANOVA revealed significant effects of Drug(F(2,16) = 127.90, p � 0.0001), Lesion (F(1,16) =16.53, p � 0.001) as well as a significant interactionbetween Drug and Lesion (F(2,16) = 8.76, p � 0.01).In sham-lesioned rats, post hoc tests showed that acuteinjections of haloperidol and olanzapine significantlyincreased c-fos levels (p � 0.001 in both cases). Further-more, the level of c-fos expression induced by haloperi-dol was larger than that induced by olanzapine (p �0.01). In entorhinal cortex-lesioned rats, both treatmentssignificantly increased c-fos mRNA expression (p �0.001 in both cases); nevertheless, haloperidol-inducedc-fos expression was significantly lower than that ofsham-lesioned rats (p � 0.001).

For the core of the nucleus accumbens (Figs. 3 and4), ANOVA revealed significant effects of Drug(F(2,16) = 17.26, p � 0.001), Lesion (F(1,16) = 14.18,p � 0.01), as well as a significant interaction betweenthese two factors (F(2,16) = 4.98, p � 0.05). In sham-lesioned rats, post hoc tests showed that acute injectionsof haloperidol and olanzapine significantly increased c-fos levels (p � 0.01 and p � 0.001, respectively). Inentorhinal cortex-lesioned rats, neither haloperidol norolanzapine significantly increased c-fos mRNAexpression. Moreover, both haloperidol and olanzapine-induced c-fos expression levels were significantly lowerthan that of sham-lesioned rats (p � 0.05 and p �0.01, respectively).

For the shell of the nucleus accumbens (Figs. 3 and4), ANOVA revealed significant effects of Drug(F(2,16) = 38.12, p � 0.0001), Lesion (F(1,16) = 5.13,p � 0.05) and a significant interaction between Drug andLesion (F(2,16) = 7.50, p � 0.01). In sham-lesioned rats,


Fig. 4. Effect of haloperidol (1 mg/kg) and olanzapine (10 mg/kg) treatment on c-fos expression in sham-lesioned rats and in entorhinal cortex-lesioned rats in caudal cingulate cortex, dorsomedial and dorsolateral caudate-putamen, core and shell of the nucleus accumbens, lateral septumand central amygdala. The results are expressed as the means ± SEM of optical density. ∗: p � 0.05, ∗∗: p � 0.01 and ∗∗∗: p � 0.001 ascompared to respective vehicle injected group. #: p � 0.05, ##: p � 0.01 and ###: p � 0.001 as compared to respective sham-lesioned group.

post hoc tests showed that acute injections of haloperidoland olanzapine significantly increased c-fos levels (p� 0.001 in both cases). In entorhinal cortex-lesionedrats, both haloperidol and olanzapine significantlyincreased c-fos mRNA expression (p � 0.05 and p �0.001, respectively); nevertheless, haloperidol-inducedc-fos expression was significantly lower than that ofsham-lesioned rats (p � 0.01).

For the lateral septum (Figs. 3 and 4), ANOVArevealed a significant effect of Drug (F(2,16) = 11.21,

p � 0.001) but not of Lesion (F(1,16) = 2.42, p =0.14), nor of interaction between Drug and Lesion(F(2,16) = 2.17, p = 0.15). In sham-lesioned rats, posthoc tests showed that acute injections of haloperidol andolanzapine significantly increased c-fos levels (p �0.05 in both cases). In entorhinal cortex-lesioned rats,olanzapine but not haloperidol significantly increased c-fos mRNA expression (p � 0.05).

For the central amygdala (Fig. 4), ANOVA revealeda significant effect of Drug (F(2,13) = 5.26, p � 0.05)


Table 1Effects of entorhinal cortex lesion on haloperidol- and olanzapine-induced c-fos mRNA expression

Vehicle Haloperidol Olanzapine

Sham Ento Sham Ento Sham Ento

rCgCx 33.1 ± 2.2 30.0 ± 3.0 30.8 ± 0.9 37.6 ± 3.9 32.9 ± 1.4 34.9 ± 3.8LA 29.4 ± 0.4 33.0 ± 3.5 31.8 ± 0.9 34.9 ± 3.8 35.6 ± 2.3 31.8 ± 2.4CA1 35.6 ± 0.8 36.6 ± 3.2 38.3 ± 1.4 39.2 ± 5.0 43.0 ± 0.8 33.5 ± 2.0CA3 31.7 ± 0.9 34.8 ± 2.7 32.0 ± 1.3 36.3 ± 4.6 38.8 ± 1.4 31.5 ± 2.2DG 38.9 ± 0.8 39.7 ± 2.6 41.9 ± 2.2 44.9 ± 6.2 42.6 ± 1.3 38.1 ± 3.2

Each value represents the mean ± SEM of optical density. Abbreviations: rCgCx, rostral cingulate cortex; LA, lateral amygdala; CA1, hippocampusCA1; CA3, hippocampus CA3; DG, dendate gyrus.

but not of Lesion (F(1,13) = 0.01, p = 0.92), nor of inter-action between Drug and Lesion (F(2,13) = 2.00, p =0.18). In sham-lesioned rats, post hoc tests showed thatacute injections of olanzapine, but not of haloperidol,significantly increased c-fos levels (p � 0.05). Inentorhinal cortex-lesioned rats, neither haloperidol norolanzapine significantly modified c-fos levels.

For the lateral amygdala (Table 1), ANOVA failed toreveal significant effects of either Drug (F(2,13) =0.40, p = 0.68), Lesion (F(1,13) = 0.17, p = 0.69) orinteraction between both factors (F(2,13) = 1.06, p =0.37).

For the three hippocampal regions studied, CA1, CA3and dentate gyrus (Table 1), ANOVA failed to revealsignificant effects of either Drug (F(2,13) = 0.40, p =0.68; F(1,14) = 0.29, p = 0.75; F(2,14) = 0.84, p =0.45, respectively), Lesion (F(1,13) = 0.17, p = 0.69;F(1,14) = 0.00, p = 0.99, F(1,14) = 0.01, p = 0.93,respectively) or interaction between these two factors(F(2,13) = 1.06, p = 0.37; F(2,14) = 3.19, p = 0.07;F(2,14) = 0.71, p = 0.51, respectively).

4. Discussion

Using an in situ hybridization technique, the resultsof the present study show that haloperidol and olanzap-ine both increased the expression of c-fos in several brainareas such as the caudal cingulate cortex, dorsomedialand dorsolateral caudate-putamen, nucleus accumbenscore and shell, as well as lateral septum. In addition,olanzapine, but not haloperidol increased c-fosexpression within the central nucleus of the amygdala.Other areas (rostral cingulate cortex, lateral amygdala,CA1, CA3 and dendate gyrus) were unaffected by thesetreatments. Lesion of the entorhinal cortex affected c-fos expression in a compound- and regional-dependentmanner, since haloperidol-induced expression wasdecreased in all brain areas considered, whereas olanzap-ine-induced c-fos expression was less affected, parti-

cularly in the shell of the nucleus accumbens and in thelateral septum.

4.1. Effect of olanzapine and haloperidol on c-fosexpression in sham-lesioned rats

Increased expression of c-fos by antipsychotic com-pounds is thought to reflect their neuroanatomical tar-gets. Several studies have described regional differencesfollowing treatment with classical neuroleptic drugs suchas haloperidol and atypical antipsychotic drugs such asclozapine (Fink-Jensen and Kristensen, 1994; Hurley etal., 1996; Murphy and Feldon, 2001; Robertson et al.,1994; Semba et al., 1999). The present study confirmsand extends these data, in that it provides the first directcomparison, in a large number of brain areas, betweenc-fos expression induced by haloperidol and that inducedby an atypical antipsychotic, olanzapine, which exhibitsa very similar though not identical in vitro profile to clo-zapine (Bymaster et al., 1997). Haloperidol inducedexpression of c-fos mRNA in several areas such as thecaudal cingulate cortex, dorsolateral and dorsomedialcaudate-putamen, core and shell of nucleus accumbens,and lateral septum. Other brain areas such as the rostralcingulate, amygdala and hippocampus were unaffectedby the treatment. For the most part, the induction patternis in agreement with previous studies that used either insitu hybridization (Hurley et al., 1996; Merchant et al.,1996; Semba et al., 1999) or immunohistochemical tech-niques (Ohashi et al., 1998; Sun et al., 1998). Moreover,the lack of induction that we noted in the rostral cingu-late cortex, central amygdala and hippocampus is alsoconsistent with previous reports (Sun et al., 1998 for ros-tral cingulate; Ohashi et al., 1998 for hippocampus;Pinna and Morelli, 1999 for amygdala). Olanzapineinduced c-fos in the same brain areas as did haloperidol;in addition olanzapine induced c-fos expression in thecentral nucleus of the amygdala. To our knowledge, thepresent study is the first concerning olanzapine using insitu hybridization (except that by Fujimura et al., 2000,


which was focused on the retrosplenial cortex). Theregional pattern of c-fos expression is consistent withprevious studies that used immunohistochemical tech-niques (Ohashi et al., 2000; Robertson and Fibiger, 1996;Sebens et al., 1998). In the other brain regions investi-gated, no increase in the level of c-fos mRNA wasdetected. In contrast to previous reports, we did notobserve any c-fos mRNA transcription in the rostralcingulate cortex. This may be related to the rostro-caudallevel of the sampling used (more rostral in the presentstudy). Taken together, these data indicate that haloperi-dol and olanzapine induced c-fos expression in a similarset of brain areas, with the exception of the centralamygdala. In most of these brain areas, the two com-pounds induced quantitatively similar expression, onenoticeable exception being the dorsolateral caudate-putamen, in which haloperidol produced a higher levelof induction than olanzapine.

4.2. Effect of entorhinal cortex lesion on olanzapine-and haloperidol-induced c-fos expression

The lesion of the entorhinal cortex had no effect onthe basal expression of c-fos. Some immediate-earlygene induction produced by entorhinal cortex lesionswas found to occur shortly after surgery in severalentorhinal cortex-connected areas, but this induction wastransient and no longer observable 15 days after thelesion (Haas et al., 1999). The lack of gene expressionin our present experimental conditions (delay of 15 days)is hence consistent with this study.

By contrast, entorhinal cortex lesions modified halop-eridol- and olanzapine-induced c-fos expression in acompound- and regional-dependent manner. Haloperi-dol-induced expression was significantly reduced in mostareas: caudal cingulate cortex, dorsomedial and dorsolat-eral caudate-putamen, core and shell of the nucleusaccumbens, and lateral septum. In the dorsolateral cau-date-putamen and shell of the nucleus accumbens, thedecrease was less marked than in other areas, sinceresidual c-fos expression still significantly differed fromvehicle-injected control groups. Olanzapine-induced c-fos expression was also reduced in some but not all brainareas: significant reduction was found in the caudalcingulate cortex, dorsomedial caudate-putamen, core ofthe nucleus accumbens, and central amygdala. In con-trast, no reduction was found in the shell of the nucleusaccumbens or lateral septum.

The entorhinal cortex sends efferent fibers to all brainareas considered: cingulate cortex (Insausti et al., 1997),caudate-putamen and nucleus accumbens (Totterdell andMeredith, 1997), central amygdala (Pitkanen et al.,2000) and lateral septum (Leranth et al., 1999). The neu-rotransmitter involved is glutamate (Brothers and Finch,1985; Finch et al., 1995; Leranth et al., 1999) althoughthis has not yet been demonstrated in the case of the

cingulate cortex. It is tempting to attribute the effects ofthe lesion to the severing of these fibers. However, thisdoes not account for the region- and compound-depen-dent effects of the lesion, for example the lack ofreduction of olanzapine-induced c-fos expression in thenucleus accumbens shell and lateral septum. The follow-ing discussion examines how the pharmacological profileof haloperidol and olanzapine may contribute to the dif-ferential sensitivity to the lesion.

Although the mechanism of haloperidol-induced c-fosexpression is still a matter of debate, a functional block-ade of dopamine D2 receptors is supported by severalfindings, at least in the striatum (Dragunow et al., 1990;Miller, 1990; Robertson et al., 1992). This blockade mayresult from the suppression of the tonic inhibitionexerted by dopamine (Robertson and Fibiger, 1992) atthe presynaptic level on excitatory afferent neuronsand/or at the postsynaptic level on medium spiny neu-rons, thus allowing excitatory neurotransmitters such asglutamate to induce c-fos gene expression (Chartoff etal., 1999; De Souza and Meredith, 1999; Hussain et al.,2001; Ziolkowska and Hollt, 1993). According to thisview, the effects of entorhinal cortex lesions may be dueto: (i) suppression of haloperidol target receptors, (ii)alteration of mesolimbic and mesostriatal dopaminergicsystems, and/or (iii) removal of excitatory effect exertedby entorhinal cortex afferents. Unfortunately, we do nothave, as yet, any data relating to the modifications ofthe expression of dopamine D2 receptors followingentorhinal cortex lesions. Altered functioning of thedopaminergic system following the entorhinal cortexlesions remains controversial. Thus, increased tissueconcentration of dopamine in caudate-putamen andnucleus accumbens at puberty was reported followingneonatal excitotoxic lesion of the left entorhinal cortex(Uehara et al., 2000), but decreased dopamine level innucleus accumbens was reported following 6-OHDAlesion of the left entorhinal cortex (Louilot and Choulli,1997). Finally, no modification of either basal oramphetamine-induced release of dopamine in nucleusaccumbens was reported following electrolytic lesionsof entorhinal cortex (Coutureau et al., 2002). Thus, thedecreased c-fos expression following entorhinal cortexlesions may result from disruption of the excitatorycomponent essential for c-fos expression to occur. Gluta-matergic disturbance on dopamine-mediated immediateearly gene expression has been reported by Cenci andBjorklund (1993) who observed that striatal c-fosexpression induced by amphetamine was blocked bytransection of afferent glutamatergic fibers from the pre-frontal, prelimbic and anterior sensorimotor cortices. Itcan, nevertheless, be noted that Roe et al. (1998) foundno effect of neuronal loss in the dorsal hippocampus onthe increase in c-fos expression in the nucleus accum-bens after administration of haloperidol.

The mechanisms underlying olanzapine-induced c-fos


expression remain to be established since, unlike halop-eridol which targets preferentially dopamine D2 recep-tors, olanzapine displays high affinity for a larger num-ber of receptors, namely dopamine D1, D2, D3 and D4,serotonin 5-HT2a, 5-HT3 and 5-HT6, a-1 adrenergic,histamine H1, and muscarinic receptors (Bymaster et al.,1996). Blockade of D2 receptors could account for someolanzapine-induced c-fos expression, as this compoundwas found to block a substantial number of dopamineD2 receptors at the dose used in the present study(Bymaster et al., 1997), and as cross-tolerance occursbetween haloperidol and olanzapine in several brainareas (e.g. caudal cingulate cortex, dorsomedial caudate-putamen, core and shell of the nucleus accumbens andlateral septum; Sebens et al., 1998). Our results are con-sistent with the proposal of a common action for the twocompounds in the caudal cingulate cortex, dorsomedialcaudate-putamen and core of the nucleus accumbens,since the pattern of c-fos expression of both compoundswas similarly affected by the lesion in these areas. Otherreceptors are probably involved in brain areas such asthe central amygdala, since we found that olanzapine butnot haloperidol induced c-fos in this structure. It is note-worthy that no cross-tolerance between haloperidol andolanzapine was found in this area (Sebens et al., 1998).In the dorsolateral caudate-putamen, as the selective 5-HT2 antagonists ritanserin and ketanserin attenuate theincrease of c-fos mRNA induced by haloperidol(Ishibashi et al., 1996), the lower level of c-fos inductionin sham-lesioned rats by olanzapine as opposed to halop-eridol might result from its propensity to block serotonin5-HT2a receptors (Zhang and Bymaster, 1999). Finally,our results concerning the effect of the entorhinal lesionin the shell of the nucleus accumbens and lateral septumprovide the most striking evidence for separate targetsfor the two drugs, as in these areas the pattern of c-fosexpression of the two compounds was differently affec-ted by the lesion. Further studies are needed to definethe biological substrates of this dissociation as the effectsof olanzapine may be attributed to interactions with sev-eral receptor types. The influence of haloperidol andolanzapine on distinct sets of neurons remains the mostlikely explanation.

Taken together, our results show that bilateral entorhi-nal cortex lesions differentially affect the pattern ofregional c-fos expression induced by haloperidol andolanzapine. The results in the nucleus accumbens shelland lateral septum are of special interest since thesestructures may constitute key sites mediating the antipsy-chotic effects (Robertson et al., 1994). These results evi-dence that the effects of olanzapine and haloperidol aremediated by different mechanisms in these areas (but seeSebens et al., 1998). Indeed, in the two areas considered,c-fos expression induced by haloperidol, but not thatinduced by olanzapine, was dramatically affected by thelesion. This result emphasizes the importance of the

exploration of relationships between a given brain neuro-pathology which is intended to simulate that of neurop-sychiatric diseases and drug efficacy. Given the accumu-lating evidence, (1) for cytoarchitectonic alterationswithin the entorhinal cortex of schizophrenic patients,and (2) for experimentally induced cognitive deficits byentorhinal cortex lesions which parallel those observedin schizophrenic patients, the present data further vali-date our lesion model for studying mechanisms of anti-psychotic actions in schizophrenia.

Acknowledgements

Olanzapine was generously provided by Dr M. Nied-enthal (Eli Lilly), Indianapolis, USA. The authors wouldlike to acknowledge the technical help of Mr. O. Bild-stein and R. Paul in animal care.

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Bilateral lesions of the entorhinal cortex differentially modify haloperidol- and olanzapine-induced c-fos mRNA expression in the rat forebrain