We have designed a series of experiments to identify key biochemical differences induced by either typical (haloperiodol) or atypical (clozapine) antipsychotic drugs, administered acutely or chronically, to normal monkeys or to monkeys with bilateral lesion of the dopamine neurons terminating in the dorsolateral prefrontal cortex (to model a hypothesized deficit in schizophrenia). Employing techniques that are currently ongoing in our laboratories (including MRI-directed stereotaxic implantation of guide cannulae for microdialysis probes which allow for repeated sampling of a given region), we will initially determine the acute actions of the antipsychotic drugs, haloperidol and clozapine on the outflow of monoamine, amino acids, and peptide neurotransmitters in cortical (dorsolateral and medial prefrontal cortices, premotor and motor cortices) and subcortical (caudate, putamen, nucleus accumbens, and amygdala) regions. In chronically treated animals, assessments of extracellular levels of the aforementioned neurotransmitters/neuromodulators will be performed two weeks following the start of antipsychotic regimen and will be followed every 6 weeks for up to one year. Following acute or chronic treatment, animals will be sacrificed, the brains removed, sectioned and tissue punches removed. This punched tissue will be divided for use in (1) in vitro release studies focused on presynaptic regulation of DA release in different brain regions, (2) postmortem analysis of tissue levels of neurotensin, cholecystokinin, monoamines and their metabolites, and (3) for receptor binding studies to examine changes in dopaminergic, serotonergic, and excitatory amino acid receptors. The proposed experiments provide a powerful method of assessing the neurochemical effects of treatment with different classes of antipsychotic drugs in the non-human primate. Furthermore, analysis of lesioned brains and their responsiveness to biochemical consequences of a compromised dorsolateral prefrontal cortical dopamine system on subcortical areas, particularly the accumbens, striatum and the amygdala and provide insight into how neuroleptics might reestablish brain function in the presence of a compromised dorsolateral prefrontal cortex.
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