The guidance and resources provided by the SDA will be directed towards examining forebrain neurochemical indices in an animal model of schizophrenia-like hippocampal neuropathy. Numerous studies have revealed morphometric and neurochemical abnormalities post-mortem in the temporal lobe of schizophrenic individuals. However, the potential contribution of these abnormalities to the dopaminergic dysfunction associated with schizophrenia has been largely ignored in animal models. Anatomical and behavioral studies have indirectly implicated a functional link between excitatory hippocampal afferents and dopamine-rich cortical and subcortical areas. The experiments planned for the tenure of the SDA funding period will test a series of hypotheses in the rat regarding neurochemical changes in specific brain structures following hippocampal perturbations. In the primary set of experiments, graded hippocampal cell loss will be produced in adult rats by intracerebroventricular (ICV) injection of the excitotoxin, kainic acid. At specific post-lesion intervals, ambient and phasic neurotransmitter release will be assessed in the nucleus accumbens, corpus striatum, and prefrontal cortex. Extracellular concentrations of dopamine, glutamate and aspartate will be quantified in each brain area using state-of-the-art microdialysis techniques and high-performance liquid chromatography coupled with electrochemical detection. Quantitative autoradiography will also be used to assess the effects of hippocampal lesions on dopamine receptor binding, including the recently discovered D3 and D4 receptors, in specific brain areas. In three sets of closely related experiments, the applicant also intends to: 1) compare the neurochemical effects of lesions elsewhere in the hippocampal formation and extrahippocampal perturbations to effects observed after hippocampal KA lesions, 2) compare the neurochemical effects of perinatal excitotoxic lesions to the effects observed after hippocampal KA lesions in adults, and 3) observe the neurochemical effects of neuroleptics in hippocampally- lesioned animals. Patterns of excitatory amino acid and dopamine release will be compared between animals in each of these studies, and dopamine receptor binding will be compared between groups in the first two experiments. These studies should further define the contributions of limbic and non-limbic pathways to forebrain neurochemical functioning. More importantly, the results may further our understanding of the pathophysiology of schizophrenia and lead to the development of novel therapeutic strategies.
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