Evidence has accumulated which links changes in putative neurotransmitter functions, the cerebral macromolecules, phospholipid metabolism and membrane structure-function to narcotic addiction mechanism(s). Based on our studies and those of others, we propose to (1) study the role of gene expression on the regulation of macromolecule biosynthesis in tolerant animals and its relationship to narcotic tolerance development; (2) study the mechanism by which narcotics alter gene expression; (3) study the biochemical consequences of the narcotic-induced increase in gene expression and their relationship to tolerance development; (4) define the specific effects of chronic narcotic treatment on membrane structure and function in a well-defined neuronal pathway, since numerous pharmacologic, biochemical and neurophysiologic studies have clearly shown that narcotic treatment effects membrane function, synthesis and turnover. We hope to determine the chemical nature of some membrane constituents which are specifically altered during tolerance development to narcotics, and to further determine the role of these membrane constituents in synaptic function. At present, we do not know the causal relationship between alteration of genetic control and changes in membrane structure-function caused by chronic morphine treatment. However, these are indeed narcotic-specific phenomena because the changes can be reversed by naloxone. Therefore, the data obtained should be useful in search for the neurochemical mechanism of narcotic actions.
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