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Neurons located in the nucleus paragigantocellularis (PGi) in the rostral ventral medulla provide a strong opioid and excitatory amino acid projection to the nucleus locus coeruleus (LC) in the dorsal pontine tegmentum. The LC is solely responsible for providing norepinephrine to the forebrain and activation of neurons in this brain region has been correlated with changes in behavioral state and a general increase in sympathetic activity. Several lines of evidence have recently implicated the PGi/LC pathway in the mediation of the physical and adverse signs observed in animals upon withdrawal from opiates. Specifically, neurons in the LC of opiate dependent rats have been reported to have significant increases in their discharge rates following cessation of opiate administration or by precipitation of opiate withdrawal with an opiate antagonist. This increase in neuronal activity has been reported to be caused by an efflux of excitatory amino acids from axon terminals in the LC most likely deriving from the PGi. Activation of glutamate-containing neurons in the PGi may depend on direct synaptic activation of the morphine-like mu-opiate receptor by endogenous opioid peptides on LC-projecting neurons in the PGi which subsequently affect glutamate release in the LC. The recent production of antibodies directed against such receptors can be used to examine the sites of actions of their endogenous ligands. The specific aims of the proposed studies address fundamental questions regarding anatomical substrates responsible for mediating LC activation during opiate withdrawal. Aim 1 will examine whether the mu-selective opiate receptor is localized on (1) plasmalemmal sites of LC-projecting neurons in the PGi and (2) axon terminals which are presynaptic to LC-projecting neurons in the PGi. Aim 11 will determine the cellular substrates for proposed inter-actions between PGi afferent terminals, enkephalin afferents and the mu- selective receptor. The methods include dual labeling immunocytochemistry and tract-tracing at the electron microscopic level in adult rat brain. Ultrastructural analysis is a powerful technique to determine directly whether receptors are neuronal or glial, as well as their pre- and postsynaptic locations on identified neurons. This methodology permits the direct visualization of sites representing the functional expression of identified receptors. Ultrastructural immunocytochemical localization of neuro-transmitters and receptors also complement pharmacological and physiological studies in which direct and indirect interactions are difficult, if not impossible, to differentiate. The results will serve to verify and qualify the cellular mechanisms through which opiate receptor activation and excitatory amino acids may regulate neuronal activity in the PGi/LC pathway. Elucidation of the anatomical substrates in the medullo-coerulear circuit may provide a model for our under-standing of the neural circuits involved in drug dependence in humans. These studies will lay the necessary groundwork for future studies directed at examing potential changes in mu-opiate receptor density and distribution in naive versus opiate dependent animals.

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