The long term goal of the proposed research is to generate guiding principles for interpretation of the role of telencephalic opioid peptides in brain and behavioral mechanisms. Efforts toward this understanding involve the effects of convulsant and psychoactive drugs on the structure and function of identified opioid peptidergic pathways in the cerebral cortex, hippocampal formation, and basal ganglia of rats. First, in adult and developing rats, immunohistochemistry and in situ hybridization histochemistry will be used to determine the similarities and distinctions between the telencephalic neuronal systems containing prodynorphin and/or proenkephalin. Opioid peptide immunocytochemistry will be combined with immunostaining of Substance P and glutamic acid decarboxylase in order to determine possible colocalization of these substances with the opioids in overlapping forebrain systems. Second, regulation of the expression of opioid peptides in identified pathways will be explored in hippocampal transplants and in normal limbic cortex. A third series of experiments is based on the recently demonstrated ability of the dopamirergic agonist, apomorphine, to increase the synthesis of dynorphin and substance P in striatonigral neurons. To explore the hypothesis that the apomorphine effect is mediated by cholinergic activity, administration of a cholinergic agonist and antagonist will be combined with repeated apomorphine injections in an attempt to modify the apomorphine-induced increase in striatal dynorphin and Substance P. Immunocytochemistry and in situ hybridization histochemistry will be employed to determine alterations in the biosynthesis of telencephalic opioid peptides at the cellular lever. With the combined use of immunochemical and molecular neurobiological tools, these studies will continue the efforts to define the functional organization and drug-induced metabolic responsiveness of the telencephalic systems which certain opioid peptides.
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