Effect of maternal immune activation on the kynurenine pathway in preadolescent rat offspring and on MK801-induced hyperlocomotion in adulthood: Amelioration by COX-2 inhibition Katerina Zavitsanou a,b,c,⇑ , Chai K. Lim d , Tertia Purves-Tyson b,c,e , Tim Karl b,e , Michael Kassiou f,g,h , Samuel D. Banister f,g , Gilles J. Guillemin d , Cynthia Shannon Weickert a,b,c a School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia b Neuroscience Research Australia, Randwick, NSW 2031, Australia c Schizophrenia Research Institute, Liverpool St, Darlinghurst, NSW 2011, Australia d MND and Neurodegenerative Diseases Research Centre, Australian School of Advanced Medicine (ASAM), Macquarie University, NSW 2109 Australia e School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW 2052, Australia f School of Chemistry, The University of Sydney, NSW 2006, Australia g Brain and Mind Research Institute, Sydney, NSW 2050, Australia h Discipline of Medical Radiation Sciences, University of Sydney, NSW 2006, Australia article info Article history: Received 17 March 2014 Received in revised form 1 May 2014 Accepted 19 May 2014 Available online 27 May 2014 Keywords: Kynurenine pathway PolyI:C Maternal immune activation COX-2 inhibition Celecoxib Wistar rat Adolescence Prevention abstract Infections during pregnancy and subsequent maternal immune activation (MIA) increase risk for schizo- phrenia in offspring. The progeny of rodents injected with the viral infection mimic polyI:C during ges- tation display brain and behavioural abnormalities but the underlying mechanisms are unknown. Since the blood kynurenine pathway (KP) of tryptophan degradation impacts brain function and is strongly reg- ulated by the immune system, we tested if KP changes occur in polyI:C offspring at preadolescence. We also tested whether MK801-induced hyperlocomotion, a behaviour characteristic of adult polyI:C off- spring, is prevented by adolescent treatment with celecoxib, a COX-2 inhibitor that impacts the KP. Preg- nant rats were treated with polyI:C (4 mg/kg, i.v.) or vehicle on gestational day 19. Serum levels of KP metabolites were measured in offspring of polyI:C or vehicle treated dams at postnatal day (PND) 31– 33 using HPLC/GCMS. Additional polyI:C or vehicle exposed offspring were given celecoxib or vehicle between PND 35 and 46 and tested with MK801 (0.3 mg/kg) in adulthood (PND > 90). Prenatal polyI:C resulted in increases in the serum KP neurotoxic metabolite quinolinic acid at PND 31–33 (105%, p = 0.014). In contrast, the neuroprotective kynurenic acid and its precursor kynurenine were signifi- cantly decreased (28% p = 0.027, and 31% p = 0.033, respectively). Picolinic acid, another neuroprotective KP metabolite, was increased (31%, p = 0.014). Adolescent treatment with celecoxib (2.5 and 5 mg/kg/day, i.p.) prevented the development of MK801-induced hyperlocomotion in adult polyI:C offspring. Our study reveals the blood KP as a potential mechanism by which MIA interferes with postnatal brain maturation and associated behavioural disturbances and emphasises the preventative potential of inflammation tar- geting drugs. Ó 2014 Elsevier Inc. All rights reserved. 1. Introduction Schizophrenia is considered a disorder of brain development (Insel, 2010). Although symptom onset is usually delayed until late adolescence or early adulthood, converging evidence strongly sug- gests that disruption of foetal brain development contributes to the risk of schizophrenia later in life (Weinberger, 1987). Schizophre- nia has also been shown to be associated with altered peripheral (blood) and brain inflammation markers (Dean, 2011; Fillman et al., 2013; Miller et al., 2013) and attenuating inflammation early in the disease is a promising novel approach to treatment (Muller et al., 2010). However, there is a limited understanding of how inflammatory pathways and/or their peripheral markers can pre- cipitate the onset of psychotic symptoms. A leading candidate for initiating immune changes early in development is maternal infection (Brown et al., 2009; Mednick http://dx.doi.org/10.1016/j.bbi.2014.05.011 0889-1591/Ó 2014 Elsevier Inc. All rights reserved. ⇑ Corresponding author at: Neuroscience Research Australia, Randwick, NSW 2031, Australia. Tel.: +61 2 9 399 1822; fax: +61 2 9 399 1121. E-mail address: k.zavitsanou@neura.edu.au (K. Zavitsanou). Brain, Behavior, and Immunity 41 (2014) 173–181 Contents lists available at ScienceDirect Brain, Behavior, and Immunity journal homepage: www.elsevier.com/locate/ybrbi