hydrocannabinol (THC) and the potentially anti-psychotic-likecannabidiol (CBD). Thus, we investigated the behavioural effectsof chronic adolescent THC exposure and chronic adult cannabidioltreatment in heterozygous transmembrane domain neuregulin 1mutant mice (Nrg1 HET). NRG1 is a susceptibility gene forschizophrenia.Methods: Adolescent male Nrg1 HET mice and their wild type-like(WT) littermates received vehicle or THC (10 mg/kg i.p.) for 21 dayswhereas an adult cohort was treated with vehicle or CBD (1, 50,100 mg/kg). On the first day of treatment and throughout chronictreatment, behavioural tests were performed to assess locomotion,anxiety, prepulse inhibition, cognition and memory as well as socialinteraction.Results: Nrg1 HET and WT mice were equally sensitive to thelocomotor suppressant effects of adolescent THC. THC decreased thestartle response, but there were no main effects of treatment orgenotype on prepulse inhibition. THC had cognition-impairing andsocial interaction-suppressing effects only in WT mice. Chronicexposure to high dose CBD attenuated the hyperlocomotor activityand prepulse inhibition deficit observed in vehicle-treated Nrg1 HETmice.Discussion: Male Nrg1 HET mice exposed to THC during earlyadolescence appear to be less sensitive to some of its behaviouraleffects than WT mice. Importantly, chronic treatment with CBDcould partially rescue some of the behavioural abnormalitiesobserved in this mouse model for Nrg1.

doi:10.1016/j.schres.2010.02.705

Poster 211EFFECTS OF SYSTEMIC PHENCYCLIDINE ON NEURONAL ACTIVITYOF VENTRAL TEGMENTAL AREA IN A CLASSICAL CONDITIONINGPARADIGM

Tadahiro Katayama, Eiichi Jodo, Masahiro Okamoto, Yoshiaki Suzuki,Ken-Yo Hoshino, Yukihiko KayamaDept. of Neurophysiology, Neuropsychiatry, Fukushima MedicalUniversity School of Medicine Fukushima, Fukushima, Japan

Background: Patients with schizophrenia exhibit deficits inmotivation and learning, which suggests impairment in the rewardsystem. Many studies have reported that phencyclidine (PCP) alsoinduces schizophrenia-like negative symptoms, such as reducedmotivation, blunted affect and social withdrawal in both human andanimals. PCP-administered animals are therefore considered to be areliable pharmacological model of schizophrenia. The pathophy-siology of PCP-induced disturbances in motivation and learning,however, remains still unknown. Previous studies indicated that thedopaminergic neurons in the ventral tegmental area (VTA) play apivotal role in the development of reward-associated learning andmotivation. However, there is no study so far that examines theeffects of PCP on firing activity of VTA neurons in a classicalconditioning paradigm. In the present study we recorded for thefirst time the unit activity of VTA neurons in freely-moving ratsbefore and after systemic administration of PCP in a classicalconditioning paradigm.Methods: Adult male Sprague–Dawley rats were used as subjects. Acommercial micromanipulator with a tungsten microelectrode wasused to record single-unit activity in the VTA. The recording electrodewas lowered unilaterally into the right VTA, and the micromanipu-lator was then fixed onto the cranium using dental cement.Conditioning sessions were started at least 2 weeks after surgery.Two tones (1000 Hz, 2000 Hz)were sequentially presented, inwhich

one of the two tones (CS+) was followed by the unconditionedstimulus. Intracranial stimulation to themedial forebrain bundlewasgiven as an unconditioned stimulus immediately after cessation ofthe target tone. The CS+ tonewas presented with probability 30% ofall trials. The total number of tone presentation (trials) was 400 inone conditioning session. Recording sessions were performed on thenext day after conditioning sessions. After the first recording session,animals received an intraperitoneal injection of a subanesthetic doseof 10 mg/kg PCP or 1 ml/kg physiological saline. The second and thirdsession was started 15 and 180 min after injection of PCP or saline.The total number of tone presentation (trials) was 200 in onerecording session. To analyze the firing activity of recorded neuronsfor conditioned auditory stimuli, we generated cumulative peristi-mulus time histograms (PSTHs, 10 msec bin width) for each neuronsampled from 2 sec before to 3 sec after each tone presentation. Thebaseline period was defined as the 2 sec period preceding the tonepresentation.Results: Most of VTA neurons exhibited clear phasic excitation toCS+. Systemic PCP considerably reduced such phasic responsesto both conditioned stimuli (CS+, CS-), regardless of whetherthe spontaneous activity of neurons was affected by PCP or not.The responsiveness of neurons to CS+ recovered 180 min after PCPinjection.Discussion: Our present results indicate that PCP may affect firingactivity of VTA neurons, which are involved in motivation andlearning. Therefore, repeated-alteration of VTA activity by repeatedadministration of PCP may induce long-lasting changes in neuralcircuits to induce disturbed motivation.

doi:10.1016/j.schres.2010.02.706

Poster 212THE EFFECTS OF THE CANNABINOID CB2 RECEPTOR ANTAGONIST,AM630, ON ISOLATION REARING-INDUCED BEHAVIOURALDEFICITS IN RATS

Asma Khan, David A. Kendall, Kevin C.F. FoneSchool of Biomedical Sciences, Institute of Neuroscience, Queen's MedicalCentre, University of Nottingham Nottingham, Nottinghamshire,United Kingdom

Background: Exposure to early-life adversity is thought to be a riskfactor for the development of schizophrenia. In the last decademuch attention has also focused on the potential role ofendocannabinoids (ECs) in the pathogenesis of schizophrenia. Thepresent study examined whether the CB2 receptor selectiveantagonist AM630 (6-Iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-y l](4-methoxyphenyl)methanone; CB2 antagonist)can reverse the behavioural defects elicited by rearing rats in socialisolation (a developmental model of schizophrenia).Methods: Male Lister-hooded rats were weaned on postnatal day(PND) 22-24 and half of each litter either group housed (3-4/cage; n=9) or socially isolated (SI; n=9) for 5 weeks, duringwhich they received minimal handling but had visual, auditoryand olfactory interaction with each other. Rats were injectedwith either AM630 (1 mg/kg; i.p; n=10) or saline once daily for7 consecutive days in the first week of isolation. On PND 61novel cage-induced locomotor activity (LMA) was recorded inautomated infrared activity boxes. On PND 66 all rats werehabituated to individual test arenas for 1 hr and on day 67 twotrial novel object recognition (NOR) was assessed in same arenausing a 2 h intra trial interval (ITI). On PND 81 the conditionedemotional response (CER) was monitored by placing individual

Abstracts 391

rats into the light compartment of a two chamber CER apparatus,following transfer into the dark side they were conditioned byreceiving light and tone paired with a mild unavoidable footshock on three occasions. On return to the dark side of thechamber 24 and 48 h later the total time spent freezing wasrecorded to monitor learning and memory.Results: Isolated animals exhibited hyperactivity during the first30 minutes of LMA compared with GH controls (477.7+130.6 vs609.6+165.6 counts, respectively) but this just failed to reachstatistical significance (p>0.05 by one-way ANOVA). AM630 hadno significant effect on LMA. Saline injected GH rats successfullydiscriminated the novel object (p<0.001 by Student's t-testbetween novel and familiar object) exploring this for signifi-cantly longer than the familiar in the second trial. NOR washowever impaired in saline treated SI rats which could notdiscriminate the familiar and novel objects in choice trial. ThisNOR deficit was not reversed by AM630 in SI rats (p>0.05). GHcontrols froze significantly longer than SI rats irrespective ofwhether they had received AM630 or not both at 24 h and 48 hafter the foot shock in the CER (p<0.01 by 2 way ANOVArepeated measures).Discussion: SI produced the expected hyperactivity in a novelarena and cognitive deficits in both novel object recognitionand contextual fear conditioning, consistent with this being avaluable model of schizophrenia but none of these alterationswere reversed by acute treatment with a CB2 receptor antago-nist. CB2 receptors are possibly not involved in the long lastingbehavioural defects produced by this neurodevelopmentalmodulation in rats.

doi:10.1016/j.schres.2010.02.707

Poster 213THE TIMING OF PRENATAL IMMUNE CHALLENGE DETERMINESTHE EXTENT OF WHITE MATTER MICROSTRUCTURAL ANOMALIESRELEVANT TO SCHIZOPHRENIA

Grainne M. McAlonan1, Charlton Cheung1, Qi Li1, Cheung Vinci2,Edward S.K. Hui1, Wei Ran1, Priscilla Wong3, Siew E. Chua1,Ed. X. Wu11University of Hong Kong, Hong Kong, Hong Kong; 2PolytechnicUniversity, Hong Kong, Hong Kong; 3Cornell University Ithaca, NewYork, USA

Background: Imaging and neuropathological studies point to theonset of pathology in neurodevelopmental disorders such as schizo-phrenia early in fetal life. White matter connections appear to bedisrupted, leading to altered functional connectivity during higher-order cognitive processing. We have previously reported diffusiontensor imaging (DTI) evidence of microstructural pathology in ourclinical studies of schizophrenia at first-episode and prior to drugtreatment, but direct evidence for a fetal trigger of these brainstructural differences is sparse. Epidemiological studies implicatematernal inflammation during prenatal life as an environmental riskfactor for schizophrenia in the offspring. In this study we tested thehypothesis that maternal immune activation causes post-natal whitematter microstructural anomalies in offspring relevant to schizophre-nia or autism. We examined the effects of maternal inflammation inearly and late gestation on white matter microstructure in theoffspring using advanced in-vivo MR-DTI.Methods: We used an mouse model of maternal immune activation(MIA) by the viral mimic PolyI:C administered in early (day 9) or late

(day 17) gestation. A novel application of automated voxel-basedmorphometry (VBM) of in-vivo MRI data mapped fractional aniso-tropy (FA, directional diffusionofwater) acrosswhitematterpathwaysof adult offspring. Region-of-interest manual tracing was used toconfirm FA changes in selected white matter tracts. In addition weconducted a preliminary immunohistochemical exploration of theoligodendrocyte marker CNPase to determine whether myelinationprocesses might contribute to any changes in FA observed.Results: FA was lower in MIA exposed offspring throughout fronto-striatal-limbic circuits and in the corpus callosum. Regions withlower FA were more extensive in the early exposed group. In bothgroups there were regions with increased FA but again, these weremore extensive in the early exposed group. Preliminary immuno-histochemical evidence revealed reduction in the oligodendrocytemarker CNPase in mice exposed to MIA, consistent with a whitematter structural insult affecting myelination.Discussion: The present results provide direct experimentalevidence that prenatal inflammation causes white matter micro-structural abnormalities analogous to those found in schizophrenia.Maternal inflammation earlier in gestation precipitates moreextensive changes in offspring, suggesting that the fetus is morevulnerable to environmental insults associated with schizophreniaearly in development.

doi:10.1016/j.schres.2010.02.708

Poster 214CHRONIC CLOZAPINE TREATMENT IMPROVES PRENATALINFECTION-INDUCED WORKING MEMORY DEFICITS WITHOUTINFLUENCING ADULT HIPPOCAMPAL NEUROGENESIS

Urs Meyer, Irene Knuesel, Myriel Nyffeler, Joram FeldonSwiss Federal Institute of Technology (ETH), Zurich Schwerzenbach,Switzerland

Background: Converging evidence indicates that prenatal exposureto immune challenge can induce long-term cognitive deficitsrelevant to schizophrenia. Such cognitive impairments may berelated to deficient hippocampal neurogenesis at adult age. In thepresent study, we sought evidence for the possibility that chronictreatment with the reference atypical antipsychotic drug clozapinemay improve prenatal infection-induced cognitive dysfunctions bystimulating adult hippocampal neurogenesis.Methods: To induce a viral-like acute phase response in lategestation, pregnant C57BL/6 mice on gestation day (GD) 17 weretreated with the synthetic analogue of double-stranded RNA,polyriboinosinic-polyribocytidilic acid (PolyI:C; 5 mg/kg, i.v.).Control mothers received vehicle (saline) solution only. Theresulting offspring were then subjected to chronic clozapine(CLZ; 5 mg/kg/day, i.p.) or vehicle (VEH) treatment when theyreached the adult stage of development, i.e., for 3 weeks startingfrom postnatal day (PND) 85 to 106. One day following cessation ofthe chronic drug regime, all offspring were injected with bromo-deoxyuridine (BrdU; 50 mg/kg, i.p.) twice daily on three subse-quent days (PND 107-109). The offspring were then subjected tocognitive testing in a spatial working memory task on the nexteight days (PND 100-118). Two days after completion of cognitivetesting (PND 120), all animals were sacrificed for the purpose ofimmunohistochemical evaluation of BrdU and doublecortin (DCX)expression in the dentate gyrus.Results: We found that maternal PolyI:C –induced immunechallenge led to significant spatial working memory impairmentand reduced hippocampal neurogenesis in the resulting offspring at

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