Research in the cannabinoid field has generated a voluminous literature, however, a significant gap in our knowledge of these substances is an understanding of their mechanism of action at the molecular level. The major goal of thus project is to better elucidate the biochemical events involved in the many effects of cannabis with a view toward understanding these processes at the most fundamental level possible. This proposal is to be coordinated with other support from NIDA. Several approaches will be utilized involving both biochemical and biophysical techniques; the model systems will be primarily in vitro e.g. cell culture, synaptosomes, natural and artificial membranes and """"""""isolated"""""""" enzymes. Specifically, the hypothesis we have developed that THC is a """"""""cholesteromimetic"""""""" agent will be explored. This is based on the structural similarities of THC and cholesterol and on several specific experimental observations such as the inhibition of cholesterol esterases by THC. It is possible that THC can compete with cholesterol in specific enzymic and/or physicochemical process e.g., neurotransmitter transport across synaptic membranes, monoamine oxidase activity, binding of cholesterol to various proteins, simulation of phospholipases, etc. Chemical measurements on these types of systems will be compared with physical studies using differential scanning microcalorimetry. This combined approach, hopefully, will provide a molecular picture of cannabis action and give us a fundamental understanding of how this drug used by so many in our society produces its effects. Earlier projects concentrated mainly on cannabinoid metabolites. As a continuation of this effort we plan to look for the formation of metabolites resulting from the combining of THC and various biogenic amines. If these types of metabolites are found they would likely be of great significance for our understanding of the mechanism of action of THC in vivo.
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