The aim of this project is to investigate the role of central noradrenergic systems in the opiate withdrawal syndrome and the mechanism by which clonidine suppresses this syndrome. Studies in rats, monkeys, and human subjects have supported the idea that brain noradrenergic systems are hyperactive during the opiate withdrawal syndrome and are suppressed by low doses of the alpha-2-noradrenergic agonist, clonidine. These alterations have been confirmed by studies demonstrating changes in neuronal activity in the largest noradrenergic nucleus, the locus coeruleus, and by corresponding biochemical changes in norepinephrine (NE) turnover in rat brain and by changes in the NE metabolite, MHPG, in brain, CSF, and plasma in monkeys and in plasma of human subjects. The proposed studies seek to determine whether morphine actions on noradrenergic systems are responsible for the physiological manifestations of the withdrawal syndrome. Methods are aimed at demonstrating neuroanatomical and receptor specificity of morphine and withdrawal-suppressing effects of clonidine. Four groups of studies involving (1) functional inactivation and (2) activation of the necleus locus coeruleus to assess its role in opiate withdrawal and the actions of morphine and clonidine, (3) studies of the receptor specificity of clonidine's actions, and (4) biochemical measures associated with compensatory changes in noradrenergic function which could result from chronic suppression by morphine (beta and alpha receptor-linked changes in specific brain areas). Biochemical, pharmacological, neurophysioligical, histological, and behavioral techniques will be employed. Rats will be used where possible to determine and refine biochemcial methods, but many neurophysiological and pharmacological studies will be conducted in primates because of differences between rodents and primates in the neurophysiology, biochemistry, and neuroanatomy of noradrenergic systems and the greater behavioral and physiological similarities between primate species in the manifestations of the opiate withdrawal syndrome, nordrenergic system activation, and biochemistry. The data obtained may therefore elucidate the extent and nature of NE involvement in morphine and clonidine effects in humans, support the validity of methodologies that can be applied to human studies, and provide information regarding basic mechanisms of opiate dependence and withdrawal.
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