ORIGINAL INVESTIGATION

Alterations in prefrontal glutamatergic and noradrenergicsystems following MK-801 administration in ratsprenatally exposed to methylazoxymethanolat gestational day 17

Isabelle Léna & Aline Chessel & Gwenaëlle Le Pen &

Marie-Odile Krebs & René Garcia

Received: 22 September 2006 /Accepted: 19 January 2007 / Published online: 6 February 2007# Springer-Verlag 2007

AbstractRationale Prenatal methylazoxymethanol (MAM) adminis-tration at gestational day 17 has been shown to induce inadult rats schizophrenia-like behaviours as well as morpho-logical and/or functional abnormalities in structures such asthe hippocampus, medial prefrontal cortex (mPFC) andnucleus accumbens (NAcc), consistent with human data.Objectives The aim of the present study was to furthercharacterize the neurochemical alterations associated withthis neurodevelopmental animal model of schizophrenia.Materials and methods We performed simultaneous mea-surements of locomotor activity and extracellular concen-trations of glutamate, dopamine and noradrenaline in themPFC and the NAcc of adult rats prenatally exposed toMAM or saline after acute systemic injection of a noncom-petitive NMDA antagonist, MK-801 (0.1 mg/kg s.c.).Results A significant attenuation of the MK-801-inducedincrease in glutamate levels associated with a potentiationof the increase in noradrenaline concentrations was foundin the mPFC of MAM-exposed rats, whereas no significantchange was observed in the NAcc. MAM-exposed rats alsoexhibited an exaggerated locomotor hyperactivity, in linewith the exacerbation of symptoms reported in schizo-

phrenic patients after administration of noncompetitiveNMDA antagonists.Conclusions Given the importance of the mPFC in regu-lating the hyperlocomotor effect of NMDA antagonists, ourresults suggest that the prefrontal neurochemical alterationsinduced by MK-801 may sustain the exaggerated locomotorresponse in MAM-exposed rats.

Keywords Schizophrenia . Neurodevelopment .

Catecholamines . Glutamate .Microdialysis . Locomotion .

NMDA antagonist

Introduction

Abnormal brain development involving both environmentaland genetic factors may contribute to the etiology ofschizophrenia (Weinberger 1987; Marenco and Weinberger2000; Rapoport et al. 2005). Indeed, numerous epidemio-logical studies have shown that pre- or perinatal insultssuch as maternal infections and obstetric complicationsincreased the risk to develop schizophrenia at adolescenceor early adulthood (Mednick et al. 1988; O’Callaghan et al.1991; Geddes and Lawrie 1995; Cannon et al. 2002).Furthermore, most of the post-mortem studies examiningbrains of patients with schizophrenia have failed to observeneurodegenerative processes (Roberts et al. 1987; Falkai etal. 1988; Bruton et al. 1990; Benes 1993). More recently, ithas also been proposed that the genes identified so far asrisk factors for schizophrenia are involved in synapticplasticity or functioning and might therefore alter thedevelopment and stabilization of neural circuits (Harrisonand Weinberger 2005).

Psychopharmacology (2007) 192:373–383DOI 10.1007/s00213-007-0719-x

I. Léna (*) :A. Chessel : R. GarciaINSERM Equipe Avenir, JE 2441, Laboratoire de Neurobiologieet Psychopathologie, Université de Nice-Sophia Antipolis,Parc Valrose,06108 Nice cedex 2, Francee-mail: lena@unice.fr

G. Le Pen :M.-O. KrebsINSERM U796, Physiopathologie des Maladies Psychiatriques,Université René Descartes, Hôpital Sainte-Anne,75014 Paris, France

Structural and/or functional alterations, presumed toreflect abnormal brain development, have consistently beenfound in schizophrenic patients in several interconnectedbrain regions such as the prefrontal cortex (Weinberger etal. 1986; Akbarian et al. 1996; Glantz and Lewis 2000),hippocampus (Bogerts et al. 1985; Csernansky et al. 1998;Heckers et al. 1998; Pilowsky et al. 2006) and striatum(Laruelle et al. 1996; Breier et al. 1997; Abi-Dargham et al.1998). In particular, dysfunctions of glutamatergic and/ordopaminergic neurotransmission have been demonstratedwithin these structures (Akbarian et al. 1996; Laruelle et al.1996; Breier et al. 1997; Abi-Dargham et al. 1998;Pilowsky et al. 2006) and are thought to play a central rolein the pathophysiology of schizophrenia (Krystal et al.2003; Laruelle et al. 2003).

Different animal models based on the neurodevelopmentalhypothesis of schizophrenia have been investigated. Interest-ingly, it has been shown that neonatal excitotoxic lesion of theventral hippocampus (Lipska et al. 1993; Sams-Dodd et al.1997; Al-Amin et al. 2000; Lipska 2004) and prenatalmaternal infection (Borrell et al. 2002; Zuckerman et al.2003; Zuckerman and Weiner 2005; Shi et al. 2003; Fortieret al. 2004; Ozawa et al. 2006) led in adult animals to theemergence of abnormal behaviours relevant to the positive,negative and cognitive symptoms of schizophrenia. Disrup-tion of neurogenesis by prenatal treatment with methylazoxy-methanol (MAM), an anti-mitotic agent, has also beenexplored as a possible neurodevelopmental model ofschizophrenia. Recent studies have reported that MAMadministration at gestational day 17 produced in adult ratscognitive deficits as well as behavioural alterations believed tocorrespond to certain aspects of the positive and negativesymptoms of schizophrenia (Flagstad et al. 2004, 2005;Gourevitch et al. 2004; Penschuck et al. 2006; Moore et al.2006; Le Pen et al. 2006). Moreover, consistent with the datafound in schizophrenic subjects and mentioned above,morphological and/or functional abnormalities have beenobserved in the hippocampus, medial prefrontal cortex(mPFC) and ventral striatum of rats prenatally exposed toMAM (Flagstad et al. 2004; Gourevitch et al. 2004; Lavin etal. 2005; Penschuck et al. 2006; Moore et al. 2006). Notably,Flagstad et al. (2004) have demonstrated that acute systemicinjection of amphetamine induced an exaggerated increase ofdopamine (DA) release in the nucleus accumbens (NAcc) ofMAM-exposed rats in line with the striatal dopaminergichyper-reactivity observed in schizophrenic patients (Laruelleet al. 1996; Breier et al. 1997; Abi-Dargham et al. 1998).

The aim of the present study was to further characterisethe neurochemical alterations associated with this neuro-developmental animal model of schizophrenia. In contrastto amphetamine which only induces in human subjects thepositive symptoms of schizophrenia, noncompetitiveNMDA receptors antagonists, such as phencyclidine

(PCP) and ketamine, produce, administered acutely, a widerange of schizophrenic-like symptoms in healthy volunteersand exacerbate the preexisting symptomatology in patientswith schizophrenia (Luby et al. 1959; Krystal et al. 1994;Lahti et al. 1995; Malhotra et al. 1997). We have, therefore,hypothesized that acute systemic injection of MK 801,another noncompetitive NMDA antagonist, to MAM-exposed rats could exacerbate the neurochemical dysfunc-tions induced during brain development by prenatalexposure to MAM. In rodents, NMDA antagonists appearto exert their disruptive effects on behaviour through theactivation of glutamatergic (at non-NMDA receptors),dopaminergic and noradrenergic transmission (Loscherand Honack 1992; Ouagazzal et al. 1993; Verma andMoghaddam 1996; Adams and Moghaddam 1998; Harkinet al. 2001; Takahata and Moghaddam 2003; Lorrain et al.2003b). Using in vivo microdialysis, we therefore exam-ined the effects induced by MK-801 on the extracellularlevels of glutamate, DA and noradrenaline (NA) in themPFC and the NAcc of adult rats prenatally exposed toMAM at gestational day 17. Simultaneously, the time-course effect of MK-801 on locomotor activity wasdetermined and used as a measure of behavioural abnor-malities relevant to the positive symptoms of schizophrenia(Sams-Dodd 1996; Takahata and Moghaddam 2003).

Materials and methods

Animals

Pregnant Sprague–Dawley rats were obtained from CharlesRiver (Lyon, France) at embryonic day 10 (E10; the day thevaginal plug was observed was considered as day 0 ofgestation) and were housed individually. At E17, pregnantfemales were injected intraperitoneally (i.p.) with 25 mg/kgof MAM or 0.9% NaCl. Litters were weaned 21 days afterbirth, and only males were used in our experiments. Maleswere housed by groups of four or five from the same litterwith ad libitum access to food and water with a 12/12-hlight/dark cycle (lights on from 8:00 A.M. to 8:00 P.M.). FourMAM-exposed litters and four saline-exposed litters wereused per treatment group to avoid litter effects. Allexperiments were conducted in accordance with theEuropean Community Guidelines on the care and use oflaboratory animals (86/609/EEC).

Surgery

At post-natal days 56–70, rats were anaesthetised withpentobarbital (60 mg/kg i.p.) and mounted on a stereotaxicframe. Two guide cannulae (CMA microdialysis, Stockolm,Sweden) were implanted bilaterally, one in the left mPFC

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(AP from bregma, +3.0 mm; L, 1.6 mm angled 10° towardmidline; V, −2.8 mm) and the other in the right NAcc (AP,+1.4 mm; L, 0.8 mm; V, −6.2 mm) according to the atlas ofPaxinos and Watson (1986). The two guide cannulae weresecured to the skull using dental cement and two stainlesssteel screws. Rats were given 4 to 5 days to recover aftersurgical implantation and were housed individually.

In vivo microdialysis

On the day of the experiment, rats were placed in arectangular Plexigas cage (35×35×38 mm), and twoconcentric microdialysis probes (CMA/12, 500 μm diam-eter, 20 kDa cut-off) with a membrane length of 3 mm formPFC or 2 mm for NAcc were inserted into the guidecannulae. Artificial cerebrospinal fluid (NaCl, 149 mM;KCl, 2.7 mM; MgCl2, 1 mM; CaCl2, 1.2 mM; Na2HPO4,2.33 mM; NaH2PO4, 0.45 mM; pH 7.4) was perfusedthrough the probes at a constant rate of 1 μl/min. Theprobes were connected to the microperfusion syringes viaFEP tubing using a dual-channel liquid swivel (Instech,Plymouth, USA) allowing free movement of the animal inthe experimental cage. After a 4-h stabilization period,dialysates were collected every 10 min over a period of180 min and immediately stored at −80°C before analysisby capillary electrophoresis. Three samples were collectedbefore injection of MK-801 (0.1 mg/kg) or saline to ratsprenatally exposed to MAM or saline and were used todetermine the basal levels of neurotransmitters. The timedelay due to the dead volume of the microdialysis system(probe and output tubing) was taken into account tosynchronize the measurement of locomotor activity withsample collection.

Catecholamines and glutamate analysis by capillaryelectrophoresis

The concentrations of catecholamines (DA and NA) andglutamate in the dialysate samples were determined usingan automatic P/ACE™ MDQ system (Beckman–Coulter,USA) equipped with an external laser-induced fluorescence(442/490 nm, excitation/emission; Liconix, Santa Clara,CA, USA) ZETALIF detector (Picometrics, Ramonville,France) as previously described (Bert et al. 1996). Separa-tions were performed using a fused-silica capillary with aninternal diameter of 50 μm.

Naphthalene-2,3-dicarboxaldehyde (NDA) was used asthe fluorogen agent and added to the dialysates or standardsolutions with the internal standard [dihydroxybenzylamine(DHBA) or aminoadipic acid (AAD) for catecholamines orglutamate determination, respectively] and a borate/sodiumcyanide (NaCN) solution. Catecholamines or glutamateanalysis was carried out consecutively on the same samples

using 110 mM phosphate buffer (pH 7.05) or 75 mM boratebuffer (pH 9.2), respectively, at a voltage of 25 kV.

Locomotor activity

Locomotor activity of rats was measured during themicrodialysis experiments using an automated infraredbeam-based system (Colombus, USA) placed around therectangular cage. Beam interruptions were recorded every10 min. After injection of MK-801 (0.1 mg/kg) or saline torats exposed prenatally to MAM or saline, locomotoractivity was monitored for 150 min.

Drugs and reagents

NDA and NaCN were purchased from Fluka (Buchs,Switzerland). MK-801 maleate, DA, NA, DHBA, DL-glutamate, AAD, boric acid and sodium tetraborate wereobtained from Sigma (St Louis, MO, USA), and mono anddibasic sodium phosphate were from Carlo Erba (Rodano,Italia). MAM was purchased from Midwest ResearchInstitute (Kansas City, USA). MK-801 and MAM weredissolved in 0.9% saline solution and injected, subcutane-ously (s.c.) or intraperitoneally, respectively, in a volume of1 ml/kg.

Histological analysis

At the end of the experiments, animals were injected withan overdose of pentobarbital, and their brains were rapidlyremoved. Coronal sections of the brains (25 μm) wereperformed using a cryostat, then stained with cresyl violetfor verification of probe placement in the mPFC and theNAcc.

Statistical analysis

Extracellular levels of DA, NA and glutamate wereexpressed as percentages of basal levels (not corrected forin vitro recovery) ±SEM. All data were analysed using athree-way analysis of variance (ANOVA) with time as therepeated measures and with drug (MK-801 or saline) andprenatal treatment (MAM or saline) as the between-subjects factors. The fisher’s test was used for post-hoccomparisons.

Results

Histology

A schematic drawing illustrating the placement of themicrodialysis probes in the mPFC and the shell of the NAcc

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of rats prenatally exposed to saline or MAM is shown inFig. 1.

The average basal concentrations of DA, NA andglutamate in three consecutive dialysates collected, beforeany injection, from the mPFC of rats prenatally exposed tosaline were 1.58±0.44 10−10 M, 4.09±1.12 10−10 M and2.19±0.71 10−6 M, respectively. The basal levels obtainedin the mPFC of rats exposed to MAM were: 1.50±0.5710−10 M for DA, 4.84±1.27 10−10 M for NA and 2.31±0.910−6 M for glutamate. Of note, these basal values do notrepresent the true extracellular concentrations whose accu-rate determination requires the use of the no net fluxmethod as described by Parsons and Justice (1992).

Figure 2 shows the time-course effect of subcutaneousinjection of MK-801 at the dose of 0.1 mg/kg on theextracellular levels of dopamine in the mPFC. Three-wayANOVA revealed significant effects of drug [F(1,18)=15.62, p=0.0009] and time [F(15, 270)=3.90, p<0.0001]as well as a significant drug × time interaction [F(15, 270)=4.18, p<0.0001], but no significant prenatal treatment effect[F(1,18)=0.123, p>0.05] and no significant prenataltreatment × drug or prenatal treatment × time or prenataltreatment × drug × time interactions (all p values >0.05).Thus, MK-801 induced a significant increase in cortical DAlevels in both MAM- and saline-exposed rats, which wascomparable in magnitude (about +100–150%). The post-hoc analysis indicated significant differences in DA con-centrations in these two groups compared to the controlgroups (MAM- and saline- exposed rats treated with NaCl)from 20 to 140 min post-injection.

Acute systemic injection of MK-801 also increasedsignificantly the concentrations of NA in the mPFC ofboth MAM- and saline-exposed rats compared with controlgroups (Fig. 3). ANOVA of these data indicated significant

drug [F(1,18)=64.62, p<0.0001], time [F(15, 270)=4.36,p<0.0001] and prenatal treatment [F(1,18)=5.10, p=0.036]effects as well as significant prenatal treatment × drug [F(1,18)=7.30, p=0.014] and drug × time [F(15,270)=4.02,p<0.0001] interactions, but no other significant interac-tions. Post-hoc comparisons showed that in MAM- andsaline-exposed rats, a significant increase in NA concen-trations, as compared to control groups, was obtainedbetween 20 and 140 min after MK-801 administration.The post-hoc analysis also indicated that the MK-801-induced increase in NA levels was significantly higher(about twofold) in rats prenatally exposed to MAM than inrats exposed to saline (p<0.01).

Figure 4 shows the time-course effect of MK-801 on thecortical levels of glutamate. Three-way ANOVA indicatedsignificant drug [F(1,18)=17.43, p=0.0006], time [F(15,270)=1.81, p=0.045] and prenatal treatment [F(1,18)=4.78, p=0.049] effects as well as significant drug × time[F(15, 270)=2.02, p<0.014], prenatal treatment × drug[F(1,18)=5.18, p=0.035], prenatal treatment × time [F(15,270)=2.0, p=0.015] and prenatal treatment × drug × time[F(15, 270)=3.01, p=0.0002] interactions. Post-hoc com-parisons showed that MK-801 significantly increased theconcentrations of glutamate in the mPFC of rats prenatallyexposed to saline or MAM, compared with control groups,and revealed significant differences in the effect of MK-801between MAM- and saline-exposed rats. The increase inglutamate levels, contrary to the MK-801-induced increasein cortical NA release, was significantly attenuated in ratsprenatally exposed to MAM compared with those exposedto saline. A maximal increase of about 60% in glutamateconcentrations was reached for MAM-exposed rats com-pared to 180% for saline-exposed rats. Furthermore, thepost-hoc analysis indicated that the pattern of glutamate

Fig. 1 Location of microdialy-sis probes in (a) the medialprefrontal cortex and (b) theshell of the nucleus accumbens.The schematic drawing adaptedfrom the atlas of Paxinos andWatson (1986) represents thetracts of the dialysis membranes(3 mm for mPFC and 2 mm forNAcc) in rats prenatally exposedto saline (right) or MAM (left).AcbSh shell of the nucleusaccumbens; AcbC core of thenucleus accumbens

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release was different between MAM- and saline-exposedrats with maximal increase during the first hour for theformer group and during the second hour for the lattergroup.

The basal extracellular concentrations of DA, NA andglutamate in the NAcc of rats prenatally exposed to salinewere 4.41±1.47 10−10 M, 1.77±0.29 10−10 M and 1.01±0.4110−6 M, respectively. The basal levels found in the NAcc ofrats prenatally injected with MAM were: 6.05±1.78 10−10 Mfor DA, 2.11±0.40 10−10 M for NA and 1.40±0.65 10−6 Mfor glutamate.

As shown in Fig. 5, acute subcutaneous injection of0.1 mg/kg of MK-801 did not produce significant change inthe extracellular levels of DA in the NAcc of rats prenatallyexposed to MAM or saline compared with control groups.

Statistical analysis of these data indicated, however, a trendtowards a drug effect [F(1,18)=3.99, p=0.061], but nosignificant effects of time [F(15, 270)=0.68, p=0.80] andprenatal treatment [F(1,18)=0.58, p=0.45] and no signifi-cant interactions (all p values >0.05).

Contrary to DA levels, the concentrations of NAsignificantly increased in the NAcc of rats prenatallyexposed to MAM or saline after injection of MK-801compared to control groups (Fig. 6). Indeed, three-wayANOVA revealed a significant effect of drug [F(1,18)=15.04, p=0.0011], but no significant effects of time [F(15,

Fig. 4 Time-course effect of MK-801 or saline on the extracellularlevels of glutamate in the mPFC of adult rats prenatally exposed toMAM or saline. Values are expressed as percentage (mean±SEM) ofthe three basal values obtained before injection (n=5–6 pergroup). Filled star p <0.05 vs prenatal NaCl/MK-801 at the samepost-injection time (Fisher’s test)

Fig. 5 Time-course effect of MK-801 or saline on the extracellularlevels of dopamine in the NAc of adult rats prenatally exposed toMAM or saline. Values are expressed as percentage (mean±SEM) ofthe three basal values obtained before injection (n=5–6 per group)

Fig. 3 Time-course effect of MK-801 or saline on the extracellularlevels of noradrenaline in the mPFC of adult rats prenatally exposed toMAM or saline. Values are expressed as percentage (mean±SEM) ofthe three basal values obtained before injection (n=5–6 per group).Filled star p<0.01 prenatal MAM/MK-801 vs prenatal NaCl/MK-801(Fisher’s test)

Fig. 2 Time-course effect of MK-801 or saline on the extracellularlevels of dopamine in the mPFC of adult rats prenatally exposed toMAM or saline. Values are expressed as percentage (mean±SEM) ofthe three basal values obtained before injection (n=5–6 per group)

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270)=1.04, p=0.41] and prenatal treatment [F(1,18)=1.51,p=0.23] as well as no significant interactions (all p values>0.05). The maximal increase in NA levels was about 30%above basal levels for saline-exposed rats and 50% forMAM-exposed rats.

MK-801 also induced a significant increase in theextracellular levels of glutamate in both MAM- and saline-exposed rats compared to control groups (Fig. 7). Statisticalanalysis indeed showed significant drug [F(1,18)=9.59, p=0.0059] and time [F(15, 270)=2.92, p=0.0003] effects aswell as a significant drug × time interaction [F(15, 270)=2.26, p=0.005], but no significant prenatal treatment effect[F(1,18)=0.21, p>0.05] and no significant prenatal treat-ment × drug or prenatal treatment × time or prenatal

treatment × drug × time interactions (all p values >0.05). Inboth groups, the concentrations of glutamate increasedgradually after MK-801 injection and were significantlydifferent from those of control groups at 10 min post-injection until the end of the experiment. This increase wascomparable in magnitude to that observed in the mPFC ofsaline-exposed rats.

Figure 8 illustrates the time-course effect of MK-801 atthe dose of 0.1 mg/kg s.c. on locomotion in the sameexperimental groups of rats than those used in the micro-dialysis experiments, as locomotor activity was measuredduring microdialysis. MK-801 induced a hyperlocomotionin both MAM- and saline-exposed rats compared withcontrol groups. This hyperlocomotor effect was significant-ly more pronounced in rats prenatally exposed to MAMthan in rats exposed to saline as revealed by a three-wayANOVA indicating significant effects of drug [F(1,18)=13.49, p=0.0016], time [F(15, 270)=11.08, p<0.0001] andprenatal treatment [F(1,18)=4.55, p=0.046] as well assignificant drug × time [F(15, 270)=2.12, p=0.006] andprenatal treatment × time [F(15, 270)=9.16, p<0.0001]interactions, but no other significant interactions.

Discussion

The present study demonstrates that prenatal exposure toMAM at day 17 of gestation induces neurodevelopmentalchanges leading, in adult rats, to neurochemical andbehavioural alterations in response to a noncompetitiveNMDA antagonist, MK-801. The neurochemical alterationswere observed in the mPFC, but not in the NAcc of MAM-exposed rats, and were associated with an exaggeratedstimulation of locomotor behaviour.

Fig. 7 Time-course effect of MK-801 or saline on the extracellularlevels of glutamate in the NAc of adult rats prenatally exposed toMAM or saline. Values are expressed as percentage (mean±SEM) ofthe three basal values obtained before injection (n=5–6 per group)

Fig. 6 Time-course effect of MK-801 or saline on the extracellularlevels of noradrenaline in the NAc of adult rats prenatally exposed toMAM or saline. Values are expressed as percentage (mean±SEM) ofthe three basal values obtained before injection (n=5–6 per group)

Fig. 8 Time-course effect of MK-801 or saline on locomotor activityin adult rats prenatally exposed to MAM or saline. Each pointrepresents the mean±SEM of five or six animals

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The potentiation of locomotor hyperactivity in MAM-exposed rats compared with rats prenatally exposed tosaline after MK-801 injection is in line with the exacerba-tion of symptoms reported in schizophrenic patients afteradministration of other noncompetitive NMDA antagonistssuch as PCP or ketamine (Luby et al. 1959; Lahti et al.1995; Malhotra et al. 1997). Our finding is also consistentwith very recent studies (Penschuck et al. 2006; Moore etal. 2006; Le Pen et al. 2006) which have described anenhancement of hyperlocomotion after injection of PCP orMK-801 in adult rats prenatally exposed to MAM. It isnoteworthy that Le Pen et al. (2006) have shown that motorhyperresponsiveness to MK-801 emerged only after puber-ty. Similar post-pubertal emergence of increased motorresponsiveness to NMDA antagonists has been found inother neurodevelopmental animal models such as neonatalhippocampal lesion or prenatal maternal infection (Kato etal. 2000; Al-Amin et al. 2000, 2001; Zuckerman andWeiner 2005). Collectively, these data indicate that theneurodevelopmental insults induced in these differentanimal models alter in a common way the neural circuitsinvolved in the hyperlocomotor effect of noncompetitiveNMDA antagonists, effect believed to be related to thepositive symptoms of schizophrenia. Only one of the abovestudies has, however, investigated the neurochemicalchanges associated with this behavioural abnormality (Katoet al. 2000) and has focused on the dopaminergictransmission in the NAcc (see below).

In rats prenatally exposed to saline, we found thatsystemic injection of MK-801 at the dose of 0.1 mg/kg s.c.induced an increase in the extracellular levels of DA, NAand glutamate in the mPFC associated with increased levelsof NA and glutamate in the NAcc, consistent with the resultsreported in previous microdialysis studies using MK-801(Wedzony et al. 1993; Yan et al. 1997; Mathe et al. 1998) orother noncompetitive NMDA antagonists at subanaestheticdoses (Moghaddam et al. 1997; Adams and Moghaddam1998; Lorrain et al. 2003a). The present study also extendsthe data obtained on NA system (Yan et al. 1997) to theprefrontal area and demonstrates that the effects ofnoncompetitive NMDA antagonists on NA release aremore pronounced in the mPFC than in the NAcc, similarto those observed with DA. By contrast, the absence ofsignificant change in DA concentrations in the NAcc afterMK-801 injection is not in agreement with the data ofMathe et al. (1998, 1999) showing a modest, but significantincrease in DA levels using the same dose of MK-801.Nevertheless, it should be noted that our statistical analysisindicates that the treatment effect is at the limit ofsignificance (p=0.06). Moreover, several studies (Druhanet al. 1996; Ito et al. 2006) have reported that systemicinjection of similar or higher doses of MK-801 failed toincrease DA levels in the NAcc but enhanced locomotor

activity. Of note, the placement of probes in the shell of theNAcc which receives a substantial noradrenergic innerva-tion, contrary to the core which is almost devoid of NAfibers (Berridge et al. 1997), could explained why an effectof MK-801, at the dose used here, was observed on the NAsystem but not on the DA system.

The major finding of the present study concerns theneurochemical alterations observed in the mPFC of ratsprenatally exposed to MAM after noncompetitive NMDAantagonist administration, whereas no significant alterationwas found in the NAcc. These results indicate that theprefrontal cortical neurotransmission is particularly sensi-tive not only to the effects of MAM but also to the action ofnoncompetitive NMDA antagonists. More specifically,prenatal MAM injection led, in the mPFC of adult rats, toa potentiation of the effect of a noncompetitive NMDA onNA levels associated with a reduction of its effect onglutamate levels, without alteration in DA concentrations.

Interestingly, the prefrontal cortex appears to play acritical role in the disruptive effects of noncompetitiveNMDA antagonists on locomotion, as its lesion markedlydecreases the hyperlocomotor effect of these compounds(Jentsch et al. 1998; Tzschentke and Schmidt 1998). It hasalso been shown that the locomotor hyperactivity and thecortical DA release produced by PCP was abolished orreduced, respectively, by blockade of glutamatergic trans-mission at non-NMDA receptors in the mPFC (Takahataand Moghaddam 2003). Furthermore, the same authorshave demonstrated that PCP-induced hyperlocomotion wasindependent of DA release in the NAcc, consistent with thestudies quoted above and the present results. The possibleimplication of the prefrontal NA system in the motor effectsof noncompetitive NMDA antagonists has not beeninvestigated to date. Nevertheless, behavioural studies havereported that the hyperlocomotion induced by these com-pounds was suppressed by systemic administration of α1-noradrenergic antagonists or potentiated by NA reuptakeinhibitors (Loscher and Honack 1992; Mathe et al. 1996;Harkin et al. 2001; Swanson and Schoepp 2003). Thesefindings indicate, therefore, that activation of NA transmis-sion is involved in the locomotor hyperactivity produced bynoncompetitive NMDA antagonists. On the basis of thedata mentioned above, it is tempting to hypothesize that theexaggerated locomotor stimulation observed in MAM-exposed rats after MK-801 administration may be sustainedby the potentiation of increase in cortical NA release foundin these animals. Further investigations using simultaneousmeasurements of locomotor activity and neurotransmitterrelease in presence of noradrenergic antagonists arerequired to support this hypothesis. In this respect, it isnoteworthy that an overactivity of the NA system has beendescribed in some schizophrenic patients and associatedwith the expression of positive symptoms (Lake et al. 1980;

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van Kammen et al. 1989; Kemali et al. 1990; Yamamotoand Hornykiewicz 2004). Moreover, blockade of α1-noradrenergic receptors has been proposed to contribute tothe therapeutic effects of atypical antipsychotics such asclozapine (Baldessarini et al. 1992; Svensson 2000). Apreclinical study has shown furthermore that association ofα1-noradrenergic antagonists to classical antipsychoticsimproved their beneficial effects (Wadenberg et al. 2000).

The attenuation of glutamate efflux also observed in themPFC of MAM-exposed rats in response to MK-801 seemsconsistent with data obtained in schizophrenic subjectsreporting a decrease in glutamate concentrations in theprefrontal cortex (Tsai et al. 1995) and an inversecorrelation between cerebrospinal fluid glutamate levelsand positive symptoms (Faustman et al. 1999). Our findingmight be explained by a decrease in the expression and/oractivity of NMDA receptors, as it is believed to occur inschizophrenia. Indeed, although the post-mortem studiesexamining the expression of NMDA receptors in the brainsof schizophrenic patients have reported to date contradic-tory results, recent data have shown alterations in theexpression of proteins of the post-synaptic density interact-ing with the NMDA receptors in the prefrontal cortex andseveral interconnected regions (Kristiansen et al. 2007). Ithas been proposed that noncompetitive NMDA antagonistsincrease glutamate efflux by blockade of NMDA receptorslocated on inhibitory GABAergic neurons projecting toglutamatergic neurons (Moghaddam et al. 1997; Krystal etal. 2003): this disinhibition may occur locally or instructures projecting to the mPFC (Lorrain et al. 2003a).Thus, NMDA receptor hypofunction in MAM-exposed ratswould lead, in the presence of NMDA antagonists, to adecreased disinhibition on glutamatergic neurons and anattenuated release of glutamate. The functional significanceof the alteration of the glutamatergic system is, however,not clear. Indeed, a decrease in glutamate levels in themPFC would be expected to diminish activation at non-NMDA receptors, reducing therefore the disruptive effectof MK-801 on locomotion. The attenuation of the gluta-matergic response in MAM-exposed rats may be notsufficient to counteract the other alterations present in theseanimals, such as hyperactive prefrontal NA system, thatcould sustain the exaggerated locomotor response. Furtherstudies are needed to solve this issue. Of note, the reductionin MK-801-induced glutamate efflux in the mPFC was notassociated with change in glutamate efflux in the NAcc andcould be explained by the fact that the NAcc receivesglutamatergic projections not only from the mPFC but alsofrom the hippocampus and the basolateral amygdala (Zahmand Brog 1992).

Finally, the absence of significant difference betweenrats prenatally exposed to saline and those exposed toMAM in DA release in the mPFC and in DA, NA and

glutamate levels in the NAcc after MK-801 administrationdoes not exclude that higher doses of MK-801 than thedose used in the present study may induce significantalterations of these systems. These results suggest, howev-er, that these neurotransmission systems do not seem toplay a primary role in the exacerbation of locomotorbehaviour induced by MK-801 in MAM-exposed rats.Accordingly, Kato et al. (2000), mentioned previously,have shown that the exaggerated locomotor responseobserved in adult rats with a neonatal hippocampal lesionafter injection of PCP did not involve DA transmission inthe NAcc.

In conclusion, the present study demonstrates that theneurodevelopmental insults induced by prenatal MAMexposure lead, in adult rats, to dysfunctions of theneurotransmission in the mPFC, but not in the NAcc, inresponse to a noncompetitive NMDA antagonist. The MK-801-induced increase in cortical glutamate levels wasreduced, whereas the cortical NA release was potentiated.These neurochemical alterations were associated with anexaggerated locomotor hyperactivity. Given the implicationof the mPFC and the noradrenergic system in the locomotoreffects of noncompetitive NMDA antagonists, it is conceiv-able that the potentiation of cortical NA release mightunderlie the enhanced locomotor response in MAM-exposedrats. Future studies examining the interactions between thenoradrenergic and the glutamatergic systems in the mPFCwill be of particular interest in elucidating the mechanismsunderlying this abnormal behavioural response.

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