429. RALOXIFENE INDUCES SEX-SPECIFIC CHANGES IN ANXIETY- AND DOPAMINE-RELATED BEHAVIOURS IN ADOLESCENT OFFSPRING FOLLOWING PRENATAL IMMUNE ACTIVATION

Abstract Background Adolescence is a critical period for behavioural changes in schizophrenia. Psychotic symptoms often present at late adolescence. Adolescent anxiety is a risk for later psychosis. Raloxifene, an estrogen receptor modulator, can improve symptoms in women and men with schizophrenia. Maternal immune activation (MIA) is a model of schizophrenia-like dopamine dysregulation, including sensorimotor gating deficits and increased psychostimulant sensitivity. Few studies have examined sex differences in anxiety- and schizophrenia-related behaviours in the MIA model during adolescence or if intervention with raloxifene alters these behaviours. Aims & Objectives Our aim was to determine if raloxifene treatment over adolescence altered anxiety- and schizophrenia-related behaviours across adolescence in male and female MIA offspring. Method Wistar rat dams received 4mg/kg high molecular weight-polyinosinic:polycytidylic acid [HMW-poly(I:C)] or saline (n=4-5/group) on gestational day-15. Offspring were treated daily with raloxifene (5mg/kg) or placebo in cookie dough between postnatal days (PND) 30-57 (4 groups/sex: Saline/Placebo, Saline/Raloxifene, Poly(I:C)/Placebo and Poly(I:C)/Raloxifene; females, n=10-12/group; males, n=8-10/group). Open field (OF, PND43) and elevated plus maze (EPM, PND34, PND54) tests assessed anxiety-related behaviours. Prepulse inhibition (PPI), a measure of sensory motor gating, was measured on PND47-48, and amphetamine-induced locomotion (AMPH-locomotion), relatable to psychosis, on PND50-52. Results Although there was no effect of MIA or raloxifene in the OF test, a main effect of sex (P<0.001) indicated females entered the centre zone more often than males reflecting higher baseline locomotor activity in females. In the EPM test, a main effect of PND on time in open arm was due to MIA-female offspring spending more time in the open arm at late compared to early adolescence (P=0.019). There was a trend for raloxifene to prevent this increase in MIA-females (P=0.06). MIA reduced the 120dB acoustic startle response in females compared with the controls (P=0.030), and this was unchanged in males (P=0.404). In females, although MIA did not increase %PPI, MIA-offspring treated with raloxifene show significantly reduced %PPI compared to raloxifene-treated control offspring (P=0.047) and placebo-treated MIA-offspring (P=0.007). In males, there was a trend for MIA to reduce %PPI (P=0.08), but no effects of raloxifene. In late adolescence, MIA did not increase AMPH-induced locomotion in either sex (both P>0.05). However, in males AMPH-locomotion trended toward an raloxifene-induced increase in controls (P=0.057), but a raloxifene-induced reduction in MIA offspring (P=0.029). Conversely, in females, raloxifene increased AMPH-locomotion in MIA offspring compared to raloxifene-treated control offspring. Discussion & Conclusions Although we show sex-specific changes in anxiety measures, they do not reflect increased anxiety but increased baseline activity in females and an opposite response to raloxifene by early versus late adolescent MIA females. Raloxifene-induced sensorimotor deficits in female, but not male, MIA offspring, highlight sex-specific considerations for its use. Although MIA alone did not increase AMPH sensitivity, raloxifene-induced reduced AMPH sensitivity in male MIA-offspring suggests that MIA caused an underlying difference in dopaminergic neurotransmission. The variance in the behavioural data suggests that subgroups of offspring may respond differently to MIA and/or raloxifene, and this will be assessed using clustering analysis. This study highlights the importance of considering sex- and age-specific effects of raloxifene on dopamine-related symptoms in clinical studies.