The training and research program outlined in this proposal supports the application for an ADAMHA Scientist development Award for Clinicians (SDAC). The training program outline will provide the technical expertise and research experience that will allow me to develop into a well-trained neuropharmacologist with an emphasis on electrophysiological approaches to drug addiction. The overall objective of the research are directed toward establishing the hierarchical role endogenous opioid peptides may play in specific central nervous system neurophysiological processes, and to better understand the neurochemical substrates underlying reinforcing properties of opiate drugs of abuse. These studies will be focused on the unique opioid-containing circuits within a major limbic-cortical network containing several loci of prodynorphin and proenkephalin-derived peptides. Extracellular, recording techniques will be employed to investigate selected portions of an established entorhinal cortical-hippocampal- accumbens network in both anesthetized and in freely-moving preparations. In this fashion, more precise neuropharmacological knowledge will be gained regarding areas established as important in both self-stimulation and drug- seeking behavior. The objectives of these studies will be to: 1) attempt to determine whether opioid peptides contained within specific circuits of this system function as neurotransmitters; 2) whether there are unique cellular correlates of opiate seeking behavior; and 3) whether the opioid peptides and relevant opiate receptors in this telencenphalic anatomical system are critically involved in this behavior. In vivo studies will employ the use of opiate alkaloids, opioid peptides and specific opiate receptor agonists (and antagonists) applied by local iontophoresis and micropneumatic methods, as well as by i.v. or i.p. systemic routes. The role of endogenous opioids in normal synaptic processes will be investigated in vivo by electrical stimulation of opioid-containing pathways. In studies focused on freely moving animals, recordings will be made from neurons in the circuits described above (i.e. hippocampus and nucleus accumbens) in awake animals involved in a heroin self- administration protocol. Using this paradigm the cellular correlates of opiate reward phenomena will be investigated in a more relevant preparation. Taken together the proposed experimental plan will establish an integrated research and training program that will provide the opportunity for fostering my research career in drug abuse by developing scientific expertise necessary for such an endeavor.
