The goal of this research is to characterize the effects of long-term opiate administration on central adrenoreceptor function, with an overall effort aimed at clarifying the role of adrenergic mechanisms in the mediation of the physiological and behavioral changes associated with opiate abuse. Radioligand binding techniques will be used to evaluate changes in the number and/or affinity of alpha1, alpha2, and beta adrenoreceptors in specific brain areas in rats following chronic morphine treatment, including the amygdala, hypothalamus, LC, parietal cortex, hippocampus, nucleus tractus solitarius (NTS) and spinal trigeminal nucleus (STN). While receptor changes have now been documented in cortex and hippocampus in chronic morphine-treated animals, it will be important to determine whether similar alterations occur in various limbic and brainstem structures which have been linked to the mediation of abstinence signs. Extracellular recording and micropressure drug ejection studies will be carried out in vivo in parallel with the binding assays to assess the functional correlates of changes in postsynaptic alpha and beta receptors in each of the latter four structures following chronic morphine administration. Similar analyses will then be extended in the in vitro hippocampal and NTS slice preparations using both extracellular and intracellular recording methods in combination with bath superfusion of drugs. Functional changes in presynaptic alpha2 and beta receptors resulting from long-term morphine treatment will also be assessed.
A specific aim of this research effort is to examine the possibility that changes in adrenoreceptor function in specific brain regions may be involved in the formation of opiate dependence and/or figure prominently in the manifestation of opiate withdrawal. In addressing this issue, attempts will be made to temporally correlate the occurrence of changes in radioligand binding and adrenoreceptor sensitivity with the emergence of dependence on morphine and with changes in the profile of abstinence signs across time. To further explore this question, similar types of analyses will be performed following chronic treatment of animals with U-50, 488H, a selective kappa agonist which does not produce morphine-like physical dependence. The proposed research, in contributing to our understanding of the involvement of brain adrenergic mechanisms in the physiological and behavioral changes associated with opiate abuse, might help to promote effective new strategies in the treatment of narcotic dependency in man.
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