The overall goal of this proposal is to provide further evidence for a mechanism of action for cannabinoids in which prostaglandins are important mediators. Previous work has shown that THC and other cannabinoids cause major changes in arachidonic acid metabolism in a variety of systems both in vitro and in vivo. These, in turn, lead to changes in prostaglandin levels which may affect c-AMP production and/or cause neurotransmitter mediated effects. In this application, experiments are proposed which will attempt to show a casual relationship between THC-induced prostaglandin changes and catalepsy and/or motor toxicity in the mouse. The role of lipid metabolism changes during the development of, and recovery from tolerance to THC will provide a second approach to the question of mechanism. Other approaches will involve the study of THC responses in mice actively immunized against PGE2 and the study of arachidonate metabolism in mouse strains with different responses to THC. Finally, studies on the role of the major metabolite, delta1-THC- 7-oic acid, in the pharmacodynamics of THC will be continued with special regard to its inhibitory effects on prostaglandin synthesis. A better understanding of the mechanism of action of THC is needed to (1) design experiments aimed at furthering our knowledge of the health related consequences of cannabis use (2) provide a rational basis for exploring the therapeutic uses of cannabinoids and (3) improve our understanding of a unique class of drugs.
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