CELLULAR NEUROBIOLOGY OF ENDORPHINS: ROLE IN DRUG ABUSE

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The overall objectives of the research are directed toward establishing the hierarchical role endogenous opioid peptides may have on specific central nervous system neurophysiological processes, and to apply knowledge of these mechanisms to better understand the potential 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. Both extracellular and intracellular recording techniques will be employed in investigate selected portions of an established entorhinal cortical- hippocampal-accumbens network in both anesthetized, freely- moving, and in vitro 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. Persuant to my experimental goals, 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. In vitro studies will employ drug superfusion as well as local application techniques. The role of endogenous opioids in normal synaptic processes will be investigated in vivo and in vitro by electrical stimulation of opioid-containing pathways. Single-electrode voltage clamp methods will be used for analysis of the more covert voltage-dependent opioid effects. In a major committment to studies in 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.