S284 Abstracts of the 3rd Biennial Schizophrenia International Research Conference / Schizophrenia Research 136, Supplement 1 (2012) S1–S375 [4] Harvey BH, et al., Neurochem Res 2008; 33:508-17. [5] Berk M, et al., Biol Psychiatry 2008; 64:361-8. Poster #10 SOCIAL ISOLATION REARING IN RATS ALTERS PLASMA TRYPTOPHAN METABOLISM AND IS REVERSED BY SUB-CHRONIC CLOZAPINE TREATMENT Marisa Möller 1 , Jan L. Du Preez 2 , Brian H. Harvey 3 1 Division of Pharmacology, School of Pharmacy, North West University, Potchefstroom, North West, South Africa; 2 Research Unit, Drug Research and Development Focus Area, School of Pharmacy, North West University, Potchefstroom, North West, South Africa; 3 Division of Pharmacology, School of Pharmacy, North West University, Potchefstroom, North West, South Africa Background: Schizophrenia is associated with increased oxidative stress, although the source of this redox disequilibrium is unknown. Altered tryp- tophan metabolism has been described in the disorder, possibly linked to inflammation and glutamate-directed excitotoxicity. We have demonstrated that social isolation rearing (SIR) in rats, a putative neurodevelopmental animal model of schizophrenia, is associated with cognitive and other behavioural changes [1] akin to schizophrenia, as well as altered frontal cortical D 1 and NMDA receptor binding [2] and increased oxidative stress [1]. These bio-behavioural changes are reversed by antipsychotic treatment [1,2]. Tryptophan is catabolized via the kynurenine pathway to quinolinic acid (QA), a NMDA receptor agonist with excitotoxic actions; kynurenic acid (KYNA), a NMDA receptor antagonist, purported to have neuropro- tective actions; and 3-hydroxy-anthranilic acid (3OHAA), a pro-apoptotic messenger [3]. Apart from astrocytes and glia, 60% of these kynurenine metabolites originate from the periphery. Together they contribute to the neuroprotective-neurodegenerative balance in the brain, which in turn will impact on cellular redox. To explain increased oxidative stress in SIR rats and in schizophrenia, we studied whether tryptophan metabolism and neuroprotective-neurodegenerative balance are altered in post-natal SIR rats. Moreover, we also investigated whether any observed imbalance in tryptophan metabolism could be reversed with clozapine. Methods: Male Sprague-Dawley (SD) rats (10 rats/group) were used (Ethics approval number NWU-0035-08-S5). In a non-treatment arm, two groups of rats were randomly separated at weaning and exposed to either 8 weeks SIR or 8 weeks social rearing. In the treatment arm, four groups of rats exposed to either SIR or social rearing received either saline or clozapine (5mg/kg i.p) [1,2] for the last 11 days of rearing. Animals were sacrificed and plasma tryptophan, kynurenine, KYNA, anthranilic acid, 3OHAA and QA were analysed using a solid phase extraction (SPE) liquid-chromatography electrospray ionization tandem mass spectrometry method, developed and validated in our laboratory for the simultaneous detection of tryptophan and the above-mentioned metabolites [4]. The neuroprotective ratio was expressed as: Neuroprotective ratio = 1000 × plasma KYNA (μM)/plasma kynurenine (μM). Results: Plasma tryptophan, kynurenine, anthranilic acid, 3OHAA and QA were significantly elevated in treatment naive and saline treated SIR rats versus their socially reared controls, with a significant decrease in KYNA as well as a significant decrease in the neuroprotective ratio. Clozapine treat- ment significantly reversed these alterations in SIR animals, with limited effects in the socially reared controls. Discussion: SIR in rats thus significantly disrupts tryptophan metabolism via the kynurenine pathway with increased risk for neurodegenerative changes in the brain, possibly explaining the behavioural and neurochemi- cal alterations observed in SIR animals. That these changes were reversed by clozapine not only highlights a possible novel mechanism for this antipsy- chotic, but also demonstrates that the tryptophan-kynurenine pathway may represent a viable therapeutic target for the treatment of schizophrenia. References: [1] Möller M, et al., Eur Neuropsychopharmacol 2011; 21:471-83. [2] Toua C, et al., Neurosci 2010; 165:492-9. [3] Myint A, et al., J Affec Disorders 2007;98:143-151. [4] Moller M, et al., J Chromatogr B (submitted). Poster #11 THE EFFECTS OF THE DOPAMINE D1 RECEPTOR AGONIST ON ATTENTIONAL SET-SHIFTING TASK PERFORMANCE IN RATS Agnieszka Nikiforuk Department of Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland Background: The prefrontal cortex (PFC) subserves higher order executive functions, including cognitive flexibility, i.e., the ability to modify behaviour in response to altering environmental demands. This aspect of executive function is commonly assessed in humans using the Wisconsin Card Sorting Test and its modified version, the Intradimensional/Extradimensional Shift (ID/ED) task. Cognitive flexibility may also be assessed in the rodent version of the ID/ED task, i.e., in the attentional set-shifting task (ASST). In this paradigm, rats must select a bowl containing a food reward based on the ability to discriminate the odours and the media covering the bait. The ASST requires rats to initially learn a rule and form an attentional “set” within the same stimulus dimensions. At the extradimensional (ED) shift, animals must switch their attention to a new, previously irrelevant stimulus di- mension and, for example, discriminate between the odours and no longer between the media covering the bait. The ED phase, regarded as an index of cognitive flexibility, is impaired by lesions of the medial prefrontal cortex (mPFC). The beneficial action of potential cognitive enhancer in this task may predict its efficacy in disorders that are characterized by disturbances of frontal-dependent cognitive flexibility, e.g., schizophrenia. A wide body of evidence suggests that the dopamine D1 receptor in the mPFC may be important in regulating cognitive function. However, although the involve- ment of D1 receptors in working memory is well established, less is known about their role in modulation of set-shifting ability. Therefore, the aim of the present study was to examine the impact of the selective D1 receptor agonist, SKF 81297, on rats’ performance in the ASST. Methods: SKF 81297 (0.01-1 mg/kg) was administered to Sprague-Dawley rats intraperitoneally (IP) 30 min prior to the test. The number of trials required to achieve the criterion of 6 consecutive correct responses was recorded for each rat and for each discrimination phase. Data were calcu- lated using two-way mixed-design ANOVA followed by the Newman-Keuls post-hoc test. Results: The results of the present study demonstrated that acute adminis- tration of SKF 81297 facilitated rats’ performance in the ED shift stage of the ASST (ANOVA interaction: F(24,156)=8.5, p<0.001). There was, however, an inverted U-shaped relationship between SKF 81297 dose and rats’ perfor- mance, as only middle doses (0.1 and 0.3 mg/kg) were effective whereas no effect was seen after administration of either lower (0.01 mg/kg) or higher (1 mg/kg) doses. Discussion: The beneficial effects of SKF 81297 on set-shifting may have therapeutic implications for the treatment of disorders associated with frontal-dependent cognitive impairments, including schizophrenia. Acknowledgements: This work was supported by the grant POIG.01.01.02- 12-004/09 “Depresja - mechanizmy - terapia”, co-financed by the European Union from the European Fund of Regional Development (EFRD). Poster #12 EXPRESSION OF NEUROTRANSMITTER RECEPTOR AND REGULATOR GENES IN TWO BRAIN REGIONS AND PERIPHERAL BLOOD IN A NEW ANIMAL MODEL OF SCHIZOPHRENIA: THE SPONTANEOUSLY HYPERTENSIVE RATS (SHR) Marcos L. Santoro 1,2 , Camila M. Santos 2 , Vanessa K. Ota 1,2 , Mariana C. Diana 2,3 , Ary Gadelha 2,4 , Vinicius C. Mrad 1,2 , Leticia M.N. Spindola 1,2 , Jair J. Mari 2,4 , Rodrigo Bressan 2,4 , Marilia A.C. Smith 1 , Vanessa C. Abilio 2,3 , Sintia I.N. Belangero 1,2 1 Genetics Division, Department of Morphology and Genetics, Federal University of Sao Paulo (UNIFESP), Sao Paulo, SP, Brazil; 2 Interdisciplinary Laboratory of Clinical Neurosciences (LiNC), Sao Paulo, SP, Brazil; 3 Department of Pharmacology, Federal University of Sao Paulo (UNIFESP), Sao Paulo, SP, Brazil; 4 Department of Psychiatry, Federal University of São Paulo (UNIFESP), Sao Paulo, SP, Brazil Background: Schizophrenia (SCZ) is a complex mental illness that genetic and environmental factors interact to develop the disease. Dopaminergic