40.4 EFFECTIVE EARLY INTERVENTION WITH RISPERIDONE OR CLOZAPINE IN FEMALE RATS PRENATALLY EXPOSED TO POLY-I:C: MUST TAKE PLACE BEFORE THE EMERGENCE OF BEHAVIORAL ABNORMALITIES AND REQUIRES NORMALIZATION OF STRUCTURAL DEFICITS

In the last two decades, the concept of early intervention in schizophrenia has gained much attention. Although several studies showed that treatment with atypical antipsychotic drugs (APDs) in the early clinical stages of the disorder may reduce the conversion rate to first-episode psychosis, it remains unknown if intervention can halt the progression of structural brain aberrations, and whether structural abnormalities and symptom emergence are related. Given the diagnostic, ethical and methodological limitations of human studies, the efficacy and utility of early intervention are bound to remain debatable and controversial. Here we used the maternal activation model to show that prevention of behavioral abnormalities requires normalization of structural deficits and must be implemented prior to the emergence of behavioral abnormalities. On gestation day 15, pregnant dams were injected intravenously with Poly-I:C (4 mg/kg/) or saline. Eight different cohorts of poly-I:C or saline female offspring were injected with risperidone (RIS, 0.045mg/kg) or clozapine (CLOZ, 7.5mg/kg) and respective vehicle at different developmental windows. Four cohorts were injected with RIS or vehicle at 4 time windows (TW): PNDs 34–47 (TW1), PNDs 48–61 (TW2), or PNDs 106–119 (TW3), and three cohorts were injected with CLOZ at the first three windows (third window was ineffective). All animals underwent behavioral testing (latent inhibition and amphetamine-induced locomotion) and imaging about six weeks after drug cessation. Adult females exposed prenatally to poly-I:C had smaller hippocampal, striatal, and pre-fronto-cortical volumes and larger lateral ventricular volumes, as well as disrupted latent inhibition and higher amphetamine-induced activity, compared to their controls. The efficacy of a two-week ultra-low dose RIS or CLOZ treatment in preventing these behavioral and structural abnormalities in poly-I:C offspring was a function of the drug and their time of administration. RIS was effective in preventing both structural and behavioral abnormalities when administered in the first three windows, whereas at the PND 106–120 window, RIS failed to prevent both structural and behavioral abnormalities. CLOZ was effective in preventing structural and behavioral abnormalities in the first two windows but failed to prevent both already in the third window. The present results provide strong support for structure-function relationship, since behavioral deficits were prevented only if structural deficits were prevented. Furthermore, they demonstrate that intervention must be given prior to the emergence of behavioral abnormalities in order to be effective. We previously showed that whereas volumetric reductions are present from early adolescence, disrupted latent inhibition and increased amphetamine-induced activity emerges in the female offspring on PND90. We therefore expected that in the present study, RIS and CLOZ will be effective only if given before PND 90, and this was indeed found. The difference in the preventive efficacies between RIS and CLOZ most likely stem from the fact that at the doses used, RIS acts as a 5HT2A/C antagonist without dopaminergic blockade, whereas CLOZ exerts substantial DA blockade. Importantly, the prevention trajectories in females differed from those we found previously in males and will be discussed.