685. MATERNAL IMMUNE ACTIVATION AND ESTROGEN RECEPTOR MODULATION INDUCE SEX-SPECIFIC DOPAMINE-RELATED BEHAVIOURAL AND MOLECULAR ALTERATIONS IN ADULT RAT OFFSPRING

Abstract Background Maternal immune activation (MIA) recapitulates aspects of schizophrenia pathophysiology in adult offspring, including dopamine dysregulation and behavioural abnormalities comparable to those observed in individuals with schizophrenia. The selective estrogen receptor (ER) modulator, raloxifene, can improve cognition and symptom severity in women and men with schizophrenia. Though, few studies have investigated how raloxifene may exert therapeutic effects in the adult female and male mammalian brain. Aims & Objectives We sought to determine whether chronic raloxifene treatment alters dopamine-related behaviours and brain molecular measures relevant to schizophrenia in control and MIA-exposed female and male adult rats. We predicted that MIA would induce sex-specific alterations in dopamine-related behavioral and brain molecular measures, and that raloxifene would ameliorate these changes. Method MIA was induced in Wistar rat dams on gestational day 19 with high molecular weight Poly(I:C) via tail vein injection [4mg/kg, saline/poly(I:C) n=11/10]. Raloxifene (5mg/kg) was administered to offspring daily (cookies) between postnatal day (PND) 58 to 84. The cohort consisted of four groups per sex: vehicle/placebo, vehicle/raloxifene, MIA/placebo, MIA/raloxifene (n=22-30 per group per sex). Half of these animals completed behavioural tests [prepulse inhibition (PPI) and amphetamine-induced locomotion (AMPH-locomotion]. Offspring were euthanised (PND83-84), substantia nigra (SN) was dissected, and cDNA and protein (tissue lysate) prepared. Dopaminergic transcript and protein levels were measured in offspring SN using Fluidigm BiomarkTM HD system and western blots, respectively. Data were analysed using repeated measures/two-way ANOVAs. Results In female controls, raloxifene increased AMPH-locomotion, whereas in male MIA offspring, raloxifene reduced AMPH-locomotion. We did not observe overt PPI deficits in MIA offspring. However, raloxifene enhanced PPI in male MIA offspring and ameliorated increased startle responsivity in female MIA offspring. Raloxifene reduced DRD2s mRNA in female offspring with or without MIA, and increased COMT mRNA in placebo-treated male MIA offspring compared to placebo-treated controls. Discussion & Conclusions MIA offspring exhibit an underlying dopamine dysregulation that becomes evident in response to chronic raloxifene treatment and may involve selective changes in dopamine receptor expression and dopamine degradation pathways in the SN. This study highlights sexspecific behavioural responses to ER modulation, with raloxifene conferring beneficial effects on behaviours relevant to schizophrenia, including sensorimotor gating and amphetamine sensitivity, in male MIA offspring only.