The complex syndrome of schizophrenia has been related theoretically and empirically to an elementary dysfunction in stimulus filtering/selective attention and the control of behavior by context. Using artificial selection pressure on a behavioral phenotype (Latent Inhibition of LI) that reflects these key psychophysiological constructs of schizophrenia, we have generated a novel animal (rat) behavioral model of enduring cognitive behavioral deficits associated with schizophrenia, and their pharmacological corollaries. This application for renewed funding is a plan for model testing focusing on the neural system, pharmacologic, and neurotransmitter correlates of schizophrenia. Hypotheses to be tested include that selection for low LI phenotype results in a sensitive and specific analogue of the pharmacotherapy of schizophrenia; that selection-induced deficits in LI is a developmentally delayed and enduring trait; that selection for deficits in LI is associated with hemispherically lateralized alterations in limbic-striatal networks and of intrinsic dopamine (DA) and serotonin neuronal populations; and that selection for deficits in LI is related to alterations in brain neurotensin (NT) mechanisms and their response to antipsychotic drugs. Hypothesis testing will involve the following specific aims:
Specific aim #1 would develop a third replicate of LI selection and characterize behaviorally the response of LI to artificial selection. Behavioral testing would define the age dependence of the response to selection and further evaluate deficits in the prepulse inhibition (PPI) of an acoustic startle response as a genetically correlated trait.
Specific aim #2 would define the impact of a genetically selected deficit in LI on the effects of antipsychotic drugs on stimulus filtering ability. The effects on LI of typical and atypical antipsychotics, nonantipsychotics, and DA receptor agonists would be compared in the Low, High, and Control lines.
Specific aim #3 would elucidate3 the neural pathway and neurotransmitter correlates of LI selection to explore the mechanisms of schizophrenia and antipsychotic drug action. Mitochondrial markers of synaptic activity and in vivo microdialysis estimates of DA and serotonergic neuronal activity would define the neural correlates of disrupted stimulus processing and the restorative effects of antipsychotic drugs.
Specific aim #4 would determine the role of altered brain NI mechanisms in disrupted stimulus processing and the differential effects of antipsychotic drugs on disrupted versus normal stimulus filtering. Line differences in NT gene and peptide expression would be defined. The shorter term goals of this plan are to use behavioral genetic techniques to define the mechanisms of differential stimulus processing and the deficit state and genetic determinants of antipsychotic drug effects on this operation, with the longer term objective of developing a unique genetic model of the pharmacology and mechanisms of schizophrenia.
