The long term goal of the proposed research continues to be to generate guiding principles for interpretation of the role of telencephalic opioid peptides in brain and behavioral mechanisms. Efforts toward this understanding involve the characterization of convulsant and psychoactive drug effects on the gene expression of identified opioid peptidergic pathways in the limbic cortex and basal ganglia. The proposed experiments concern the effects of the psychostimulants, cocaine and amphetamine, on the expression of the opioid peptide, dynorphin, and the immediate early gene, fos (and related antigens), in the dorsal and ventral striatum, prefrontal cortex, and hippocampal formation of rats. Low, medium, and high dose regimens of cocaine and amphetamine are proposed that induce behavioral sensitization (increased locomotor activity and/or stereotypy) in rats over time. Rats receiving dose regimens that induce sensitization will be behaviorally rated and euthanized, immediately or after varying' periods of withdrawal and/or challenge, for immunocytochemistry or in situ hybridization of dynorphin and fos immunoreactivity and mRNA. A second series of experiments will assess the contribution of serotonergic and glutamatergic afferents to dynorphin and fos regulation in dorsal and ventral striatum of normal and psychostimulant-treated rats. Specific lesions of these pathways and pharmacologically selective agonists and antagonists will be used to unmask glutamatergic and serotonergic mediation of cocaine's and amphetamine's effects. Third, rats receiving dose regimens of cocaine and lidocaine that induce convulsions will be rated for seizure severity and histochemically processed for neuron-specific markers, such as dynorphin, enkephalin, fos, and protein kinase C isoforms, already demonstrated to respond to various types of seizure activity in the hippocampal formation and limbic cortex. Selective glutamatergic antagonists will be used in an attempt to block the seizures and their neurochemical sequelae. With the combined use of immunochemical and molecular neurobiological tools, these studies should contribute to the definition of the neurobiological substrates of chronic psychostimulant actions and simultaneously elicit further information about the regulation of telencephalic opioid peptide and immediate early gene expression.
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