S192 S.19 CCNP symposium – Convergence of psychosis pathways schizophrenia are supersensitive to dopamine-like drugs at doses that do not affect control individuals. There are many animal models of human psychoses associated with street drugs, brain injury, steroid use, birth injury, and gene alterations. These lead to dopamine supersensitivity and an increase in the high-affinity states of dopamine D2 receptors, or D2High, by 200–400% in striata. Mice born with gene knockouts of some possible schizophrenia susceptibility genes are also dopamine supersensitive with ele- vated D2High states; such genes include DBH, D4 receptors, GPRK6, TH, COMT, TA-1 receptors, and RGS9. These findings suggest that multiple pathways converge to elevate the D2High state in brain regions, an elevation eliciting dopamine supersensi- tivity, psychosis, and memory reduction. Up to now, the proportion of D2High states has been measured indirectly by the competition of dopamine with [ 3 H]domperidone in vitro. However, in order to detect D2High receptors directly, we now use saturation of D2 receptors with the agonist [ 3 H](+)PHNO in the absence and presence of guanine nucleotide (GN). The number of functional D2High sites removed or affected by GN is directly related to the extent of behavioral dopamine supersensi- tivity of the rats. This method is being adapted to image D2High sites that are associated with the signs and symptoms of psychosis and thereby serve as a biomarker of the psychotic state. S.19.02 Mechanisms of dopaminergic dysfunction in rats with neonatal ventral hippocampus lesions L.K. Srivastava ° , S.K. Bhardwaj, G. Flores, R. Quirion. Douglas Hospital Research Centre, Department of Psychiatry, Quebec, Canada Rats with neonatal lesion of the ventral hippocampus (nVH) are often considered as developmental model of schizophrenia due to similarities in cognitive, social and sensorimotor behaviors and sensitivity to stress and psychostimulants. Altered sensitivity of the mesolimbic dopamine system is implicated in the behaviors of nVH lesioned animals, although the mechanisms are poorly understood. Recent studies from our laboratory suggest significant structural and molecular abnormalities in the prefrontal cortex (PFC) of rats that received bilateral ibotenic acid lesion of the VH at postnatal day (PD) 7. The length of basilar dendrites and branching and the density of dendritic spines on layer 3 pyramidal neurons are significantly decreased in post-pubertal (>PD56) lesioned rats. Medium spiny neurons from the nucleus accumbens (NAcc) also show decreased spines without changes in dendritic arborization. The basal level of an immediate early gene NGFI-B (Nurr77) mRNA in nVH lesioned rats is significantly reduced in the medial PFC at post-pubertal age. No change in NGFI-B levels is seen in the NAcc; however, a differential effect of amphetamine treatment on NGFI-B is observed. Gene microarray shows altered expression of a number of PFC genes in the lesioned rats. These include genes for Homer 2, and a post-synaptic density protein Shank 1, which, along with Homer, is involved in dendritic spine formation. Given the critical role of PFC circuits in mediating cognitive behavior and subcortical dopamine functions, these results suggest that an abnormal maturation of the PFC is a key mechanism influencing the behavior of nVH lesioned animals. S.19.03 Birth injury and the psychosis pathway: insights from animal models of obstetric complications P. Boksa ° . Douglas Hospital, Dept. of Psychiatry McGill University, Montreal, Canada Epidemiological studies have provided strong evidence that schizophrenia is associated with increased obstetric complications. Our laboratory has used animal modeling to ask if specific ob- stetric complications (birth hypoxia, Caesarean section, maternal infection) can actually cause changes in brain function resembling changes in schizophrenia. We have observed long-term changes in dopaminergic function following C-section birth or C-section with added global hypoxia in the rat and guinea pig. These birth insults alter the manner in which dopaminergic function is regulated by stress at adulthood. Systemic administration of epinephrine at birth can reverse long term increases in tyrosine hydroxylase activity in C-sectioned animals, suggesting that a lack of hormonal priming at birth may play a role in producing the CNS dopaminergic changes. In other studies, we have used a rat model of maternal in- fection with bacterial endotoxin (lippolysaccharide, LPS) during pregnancy to test effects of prenatal infection on CNS function. Offspring from infected dams show CNS changes relevant to schizophrenia, including increased amphetamine-induced locomo- tion, deficits in prepulse inhibition of startle and decreases in hip- pocampal neurogenesis. These effects of prenatal infection may be mediated by inflammatory cytokines and/or fever. We have found that LPS administered to the pregnant dam increases cytokines (interleukin-1?, tumor necrosis factor-?) in the placenta, foetal blood and maternal blood, but not in foetal brain. Thus behavioral changes due to prenatal LPS are likely secondary to cytokine induction in maternal plasma and/or the placenta. In conclusion, animal models may help to define which specific mechanisms involved in a complex event like an obstetric complication are responsible for lasting CNS effects, leading to increased risk for schizophrenia. S.19.04 In vivo imaging of the D2high receptors occupancy by antipsychotics in Schizophrenia A. Graff 1 ° , D. Mamo 1,2 , S. Kapur 1,2 . 1. Centre for Addiction and Mental Health, PET Centre, Toronto, Canada; 2 University of Toronto, Department of Psychiatry, Toronto, Canada Dopamine D2-like receptors (D2) exist in a high and a low-affinity state for their natural agonist, dopamine. Recently it has been suggested that an increase in the D2high could be involved in the pathophysiology of schizophrenia. However this hasn’t been confirmed in patients by in-vivo imaging studies due to the lacking of an “agonist” D2 radioligand. [ 11 C]-(+)-PHNO is a new PET D2 “agonist” radioligand, con- sequently it shows a more accurate picture of the functionally relevant D2high in contrast to “antagonist” radioligands like [ 11 C]raclopride. This study compares the occupancy profiles of clozapine, olan- zapine and risperidone to the D2high and D2low+high affinity states using [ 11 C]-(+)-PHNO and [ 11 C]raclopride in schizophrenic patients. The mean occupancies with the three antipsychotics were at least 20% lower with [ 11 C]-(+)-PHNO than with [ 11 C]raclopride