This proposal will use behavioral genetics to explore the pharmacology and neurobiology of stimulus filtering selective attention functions and the relationship of the deficit state to defects in information processing in schizophrenia. Hypotheses to be tested are: 1) generate and behaviorally characterize lines resulting from bidirectional selection for LI phenotype; 2) define the comparative pharmacology of lines selected for low and high LI performance phenotype; 3) compare via magnetic resonance (MR) imaging and cytochrome oxidase (CO) histochemistry the structural biology and functional neuroanatomy of brains from lines of rats selected for low and high LI phenotype; 4) examine the response of populations of DA, NE and 5-HT neurons during LI acquisition and to genetic selection for low versus high LI phenotype. Selective breeding experiments with bidirectional selection for LI phenotype and replicate and control (nonselected) lines will be used to further assess the hereditability of stimulus filtering/selective attentional functioning. The phenotype distinction of lines selected for negligible vs. enhanced expression of LI will be characterized by comparison on a battery of tests of orientation, habituation, emotionality, motivation, associative learning and spatial learning and memory, and by the relationship between stimulus preexposure level and development of U. The specific stimulus processing functions undergoing selection will be defined by the generalization of line differences to stimulus gating/attentional tasks other than LI. The pharmacogenetics of defect state attentional functioning will be explored by comparison of the effects of typical and atypical antipsychotic drugs and d-amphetamine on the expression of LI in subjects from a selected line exhibiting diminished LI and from a control line. Subjects from bidirectionally selected and control lines will be compared by brain magnetic resonance imaging to define the response of structural neurobiology to selection for divergent attentional functioning and its developmental course by longitudinal, within-subject imaging. A functional neuroanatomy of LI will be explored by cytochrome oxidase (CO) histochemistry in divergent selection and control lines. LI represents an attentional task modulated by the opposing actions of limbic DA and 5-HT receptors. The role in Ll and response to selection for LI phenotype of DA neurons innervating the nucleus accumbens, in prefrontal cortex and central amygdaloid nucleus and of 5-HT innervation of the dorsal hippocampus and prefrontal cortex will be assessed by comparison of lines by in vivo microdialysis during Ll effect acquisition. Quantitative autoradiography will be used to determine in selected and control lines the comparative localization, affinity and O protein coupling of DA and 5-HT receptors.
