OPIATE PHARMACOLOGY OF MONOAMINE PATHWAYS

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The research described in this proposal is intended to characterize the neuropharmacology of opiate drugs in the hippocampus, nucleus accumbens, medial prefrontal cortex, and ventral tegmental area (area A10) of rats. We will use electrophysiological and electrochemical techniques to measure functional responses to opiate drugs and opioid peptides. Our primary hypothesis is that opiates act through multiple receptor mechanisms, but that the cellular mechanism by which any one receptor produces its effects is consistent in different brain regions and on different cellular elements. By identifying the receptor subtypes that mediate opiate effects in different regions, and by determining which neurons within a region are opiate-sensitive, we hope to explain the "anomalous" excitations that are observed in regions such as the ventral tegmental area. In addition, we intend to determine the extent to which pre- synaptic modulation of transmitter release, and postsynaptic interactions with other transmitters contribute to the overall actions of opioid peptides. We will use electrophysiological techniques to characterize the direct actions of these drugs in in vitro brain slices, single and double in oculo brain grafts, in human xenografts to the anterior chamber of the rat eye, and in situ in rats with brain stem transections. We will measure electrophysiological responses with intracellular recording from both in vitro brain slices and in oculo transplants, with in vivo electrochemical detection of the release of endogenous norepinephrine and dopamine from brain slices and transplants, and with extracellular recording of spontaneous and evoked activity. In terms of long-range objectives, we hope to characterize the specific ways in which opiates affect the electrophysiology of neuronal systems that may be involved in the rewarding effects of these drugs. Be determining the receptors that are involved, and the ways in which their activation contributes to changes in activity in dopamine-containing regions and their targets, we hope to provide an understanding of the changes in cellular activity that may underlie behavioral responses to drugs of abuse.