Despite a great deal of evidence that the noradrenergic locus coeruleus (LC) system is a key brain area involved in opiate abuse and withdrawal, and extensive knowledge concerning the actions of opiates on LC membrane properties, the effects and related mechanisms for opiates and opiate withdrawal on this nucleus in the intact, unanesthetized brain are poorly understood. Recent insights into afferent regulation of LC open the way for new investigations of opiate actions on this preeminent noradrenergic system. Experiments are proposed to study the effects of opiates on discharge of LC neurons and their major afferents, paragigantocellularis (PGI) and prepositus hypoglossi (PrH), in unanesthetized behaving rats. Effects of acute and chronic administration of morphine, and morphine withdrawal, will determined for spontaneous and sensory-evoked activity of unambiguous noradrenergic LC neurons in behaving rats. Recordings of impulse activity from PGI or PrH neurons antidromically identified as projecting to LC will document the effects of iontophoretically applied selective opiate agonists, naloxone and dextrorphan in naive and in chronically morphine treated, anesthetized subjects. In unanesthetized animals, the normative discharge characteristics of similarly identified LC-projecting PGI and PrH neurons will be determined, as well as their response to systemic acute and chronic morphine and morphine withdrawal. Possible morphine-induced changes in the excitability of afferent terminals in LC will also be examined in these animals. Responses of LC neurons to electrical stimulation of their major afferents, and the ability of amino acid antagonists to block afferent influences, will be established in waking animals. In addition, effects of locally microinfused, selective opiate agonists and antagonists on regulation of LC from these major afferents in naive and chronically morphine pretreated, unanesthetized behaving animals will be determined. These experiments will test the hypotheses that (i) opiates may have substantial impact on LC activity through altered afferent regulation of these cells, and (ii) hyperactivity of LC neurons during opiate withdrawal is caused by increased excitation from PGI, the major afferent to LC. These studies will set the stage for future experiments in which amino acid antagonists will be tested for their ability to block hyperactivity of LC during morphine withdrawal. The ability of excitatory amino acid antagonists to prevent or reverse withdrawal-induced hyperactivity in LC would be of particular clinical interest, calling for the design of such drugs for use in human opiate withdrawal programs. The long term goals of this research are to determine the effects of morphine on functionally important discharge properties of unambiguous noradrenergic LC neurons in physiologically intact animals, and to determine the sites and mechanisms by which opiates affect these cells. Such data will resolve conflicts and fill gaps in the present literature concerning the effects of this intravenously abused drug on functions of the ubiquitous noradrenergic brain system, and clarify the role of this system in opiate abuse and addiction.
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