This renewal application proposes to continue and extend cellular neurophysiological studies on opioid peptides and opiates in two brain regions containing proenkephalin- and prodynorphin-derived peptides: 1) the dentate gyrus of the hippocampus because the entorhinal cortical-to-dentate granule cell perforant path contains abundant enkephalin as a model for testing the transmitter role of endogenous opioid; 2) the nucleus accumbens septi (NACC) because of its reported role in heroin self administration, thus to be developed as a cellular model for opiate 'craving', with the final aim of testing therapeutic interventions. In both regions, the overall objective is to determine the physiological role of central opioid peptide- containing neurons in normative and opiate seeking behavior, using extracellular recording in anesthetized and freely moving animals and intracellular (current- and voltage-clamp) recording in brian slices in vitro.
Our specific aims are to: 1) Record from dentate granule cells to determine the effect of: a) opioid b) naloxone on synaptic responses to different stimulus parameters applied to perforant path and other afferent pathways; 2) Electrophysiologically characterize the properties of opioids with other neurotransmitters (e.g., glutamate, GABA, somatostatin) known to be abundant in NACC; 3) Examine the role of dopamine (DA) in responses of NACC neurons to opiates/opioids using exogenous DA, 6-hydroxydopamine, and DA antagonists, uptake blockers and releasers; 4) Record single unite an EEG activity from the NACC in freely moving rats during heroin self- administration to seek cellular correlates of drug-seeking behavior, as a cellular marker of """"""""craving"""""""" for later testing of therapeutic intervention; 5) Study opiate/opioid responsivity in animals, or slices from animals, chronically treated with morphine pellets, to seek cellular signs of tolerance and dependence for comparison to the self-administration model. These studies should help more clearly specify the role of opioid peptides and their receptors in normal, opiate-seeking and opiate addictive-tolerant behavior, perhaps provide a cellular basis for therapeusis of """"""""craving"""""""".
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