The occurrence of opiate dependence and withdrawal-represents both a major socioeconomic problem and an obstacle to the optimal use of opiates to relieve human suffering. We have discovered a restricted group of closely anatomically connected limbic structures that are selectively activated metabolically during opiate withdrawal. The pattern of activation is similar whether withdrawal is precipitated or abstinent. The temporal profile of activation of these structures during withdrawal correlates closely with the behavioral manifestations of opiate withdrawal. In addition, our findings using quantitative autoradiographic methods do not support a role for regulation of opiate receptor number or affinity as a key molecular mechanism for the emergence of dependence. We propose to extend our studies of regional cerebral glucose utilization (RCGU) by the 2-deoxyglucose (2-DG) autoradiographic method to address two additional questions: Is the development of opiate dependence and the occurrence of withdrawal dependent upon the structural and functional integrity of those limbic structures selectively activated during opiate withdrawal? Does the development of opiate dependence and withdrawal require the functional integrity of ascending noradrenergic, dopaminergic, or serotonergic forebrain systems? We will measure RCGU and behavior during precipitated withdrawal in rats with ibotenate lesions of several limbic structures and in rats with specific neurotoxic lesions of ascending noradrenergic, dopaminergic, or serotonergic neurons. In addition, we will continue to seek underlying molecular mechanisms for the development of opiate dependence by addressing the question of whether the development of opiate dependence is associated with specific regional modification of the synthesis of enkephalin. We will synthesize an oligonucleotide probe for preproenkephalin, label the probe with 125I and perform in situ hybridization studies in naive and dependent rat brains. The studies should provide important new insights into the mechanisms of opiate dependence and withdrawal, and more importantly, could provide new pharmacological approaches to the control of dependence development.
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